Natural Immunity From Omicron Strong Against Virus Subvariants: Study

Authors: Zachary Stieber via The Epoch Times, UL 18, 2022

The protection afforded by surviving COVID-19 was strong against the latest virus subvariants, including the one currently dominant in the United States, scientists in Qatar found.

People who were infected with Omicron, a variant of SARS-CoV-2, had 76.1 percent protection against symptomatic reinfection from BA.4 and BA.5 and 80 percent shielding from any reinfection, regardless of symptoms, according to the preprint study.

SARS-CoV-2, also known as the CCP (Chinese Communist Party) virus, causes COVID-19.

Omicron became the dominant virus strain in many countries in late 2021. Since then, a number of subvariants have taken hold. BA.5 is the strain currently dominant in the United States.

While protection from an Omicron infection provided robust shielding against reinfection, those who contracted a pre-Omicron strain had little protection, according to the Qatari scientists, who were led by Dr. Laith Abu-Raddad with Weill Cornell Medicine-Qatar.

Pre-Omicron infection provided just 15.1 percent effectiveness against symptomatic BA.4 and BA.5 reinfection and just 28 percent infection against any reinfection.

The scientists analyzed data from national COVID-19 databases.

Infections before Omicron were those that occurred before Dec. 19, 2021, when the variant wave started in Qatar.

Protection ‘Strong’

“Protection of a previous infection against BA.4/BA.5 reinfection was modest when the previous infection involved a pre-Omicron variant, but strong when the previous infection involved the Omicron BA.1 or BA.2 subvariant,” the scientists wrote.

Natural immunity has long been found to be superior to the protection from COVID-19 vaccines, and the new study is no exception. Vaccines provide little protection against Omicron infection and perform worse against infection and severe illness from the BA.4 and BA. 5 subvariants, studies have shown.

Natural immunity also waned against BA.4 and BA.5, highlighting how the subvariants are better at evading protection, the Qatari researchers found.

The group has been studying natural immunity for years and recently discovered that the protection from prior infection against severe disease showed no signs of waning, regardless of what strain infected the person.

Among the listed limitations for the new study was the young population of Qatar, where just 9 percent of residents are 50 years of age or older. That means the findings “may not be generalizable to other countries where elderly citizens constitute a larger proportion of the total population,” researchers wrote.

Some experts, including Abu-Raddad and U.S. Centers for Disease Control and Prevention Director Dr. Rochelle Walensky, continue recommending vaccination for people with natural immunity, pointing to studies that indicate one or more doses increase protection, but others say vaccination isn’t needed for people who survive COVID-19, since some research suggests the elevated protection is minimal and that the naturally immune are at higher risk of vaccine side effects.

Delta reinfection risk low among unvaccinated children

But scientists warn that the findings do not mean that children should not be vaccinated against COVID-19.

Authors: Heidi Ledford July 4, 2022 NATURE

Children and adolescents who had not been vaccinated against COVID-19 mounted a long-lasting immune response to infection with the Delta variant of the coronavirus SARS-CoV-2, according to a large study of Israeli health records1. The study, which has been published as a preprint on medRxiv, has not yet been peer reviewed.

A year and a half after an infection, the resulting immune response was still about 80% effective at preventing reinfection, the study found. But it isn’t clear how the results will translate to infections by coronavirus variants of the Omicron lineage, which is now dominant in many countries. “There is a much less-robust immune response to Omicron among previously infected and/or vaccinated individuals,” says Yvonne Maldonado, chief of paediatric infectious diseases at Stanford School of Medicine in California. “Such immune responses are also significantly less durable.”

Even so, the study — which includes data from about 300,000 children and adolescents — is a welcome addition to the relatively small pool of knowledge about immune responses to SARS-CoV-2 in children, says paediatrician Nigel Crawford at the Murdoch Children’s Research Institute in Melbourne, Australia, who studies vaccinology. “They’re a group for which we haven’t seen a huge amount of data to date,” he says.

When Delta dominated

The study’s authors collected data on coronavirus infections from Maccabi Healthcare Services, an Israeli health-insurance plan. They focused on the risk of infection from 1 July to 13 December 2021, when the Delta variant was dominant in Israel.

The team found that unvaccinated children and adolescents were 89% less likely to be infected with SARS-CoV-2 3–6 months after their first infection than were children who had not previously been infected. For the 12–18 age group, this protection against reinfection dropped to 82.5% from 9 months to a year after infection and remained at around that level until up to 18 months post-infection.

Children aged 5–11, however, maintained the same level of protection. That, says Crawford, could fit with observations that young children often experience milder COVID-19 than do adolescents and adults.

The study authors are now working to collect data on Omicron infections, but that analysis will be more difficult because many people in Israel switched from PCR tests to at-home rapid antigen testing in December 2021. This means that fewer positive test results have since been reported in electronic health records.

Overall, the study design is robust, says clinical data scientist Hossein Estiri at Harvard Medical School in Boston, Massachusetts. He notes that some Twitter users have picked up on the preprint and are touting it as evidence that children who have had SARS-CoV-2 infections do not need to be vaccinated. But Estiri says it’s not clear from the study how well protection from natural infection stacks up to that from vaccines, because the researchers did not include a head-to-head comparison. “This study doesn’t say that those children don’t need to be vaccinated.”

Don’t discount vaccines

And because severe COVID-19 is rare in children, the study could not make strong conclusions about protection from serious illness and hospitalization. “We know that a lot of vaccine efficacy is against severe disease,” he says.

In addition, Crawford notes that people who have both been vaccinated and had a SARS-CoV-2 infection often experience a super-charged immune response compared with those who have had only a vaccine or infection. “You wouldn’t want to rely purely on infection alone for immunity,” he says. “We have no idea what the next wave will bring.”

Self-reported outcomes, choices and discrimination among a global COVID-19 unvaccinated cohort

Authors: Robert Verkerk PhD1, Christof Plothe DO2, Naseeba Kathrada MBChB3 and
Katarina Lindley DO4, Science Unit, Alliance for Natural Health International, 78 Dorking Road, Chilworth, Surrey, GU4 8NS, United Kingdom, Praxis für Biophysikalische Osteopathie, Am Wegweiser Alzey, Germany, Dr Kats, 86 Jan Hofmeyer Road, Dawncrest, Westville, 3629, South Africa, Lindley Medical, 2100 FM 1189, Brock, Texas 76087, USA June 8, 2022

INTRODUCTION

Since COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020, there have been conflicting views among health authorities and in the published literature about the risks posed by SARS-CoV-2 to healthy populations that have not been COVID-19 injected. Additionally, health authorities and the media have frequently suggested that such unvaccinated populations pose a significant risk of infection to the COVID-19 vaccinated and vulnerable. For example, a study published in the preprint server MedRxiv found less severe outcomes among fully vaccinated COVID-19 patients requiring hospitalization, compared with those not vaccinated, yet the risk of in-hospital death was greater among the vaccinated than unvaccinated (Mielke et al 2022). A global study (68 countries) by Subramanian & Krishna (2021) found a strong tendency for countries classified as “low transmission” countries to have low rates of COVID-19 ‘vaccine’ coverage (<20%), the reverse being the case for “high transmission” countries. The UK REACT study (DHSC 2021) reported that of 98,000 volunteers studied those who were double vaccinated COVID-19 were three times less likely to test positive by PCR than those who were unvaccinated (1.21% vs 0.4%, respectively). However, the data on which such findings are based cannot demonstrate a causative relationship with vaccination owing to numerous behavioural and other confounding factors between the two groups. Furthermore, data on cases and deaths relied upon by UK authorities have been shown to be spurious owing to mis-categorisation of vaccination status (Fenton et al, 2021). There have been very few studies that either assess the health outcomes of unvaccinated populations, or compare matched unvaccinated and vaccinated populations. One such study, by Lyons-Weiler and Thomas (2020), of a paediatric patient population at an integrative clinic in Portland, Oregon, found that the health status of unvaccinated children exceeded that of those subject to the routine childhood vaccination program in the USA. However, the journal that published the study, the International Journal of Environmental

Research and Public Health, was forced to retract the study 8 months following publication
given the implications of its findings. There is a significant population of individuals and communities around the world that have not been persuaded that COVID-19 ‘genetic vaccines’ (notably the widely used mRNA or adenoviral vector based injections, sometimes referred to simply as vaccines in this paper for simplicity) are either sufficiently safe or effective to justify mass roll-out into healthy populations. This is represented by the fact that over one-third of the world’s population has yet to be COVID-19 vaccinated, the majority of these being in low-income countries (Our World In Data, 2022). In response to such concerns, a UK citizen-led cooperative, the Control Group Cooperative (CGC) (vaxcontrolgroup.com), was formed in July 2021 to represent the interests of individuals and families around the world who have chosen to not receive COVID-19 ‘vaccines.’ Among the aims of the CGC is to evaluate long-term health outcomes among the COVID-19 vaccine-free, as well as linking its members to country support networks and online community groups. Participants who join the ‘control group’ may obtain an ID card (Fig. 1), in the relevant language. The card includes the statement that the individual is part of a SARS-CoV-2 Control Group and “must not be vaccinated”. Many members have reported that these ID cards have been successful in allowing travel, preventing forced vaccination (vaccination without informed consent) or avoiding the loss of liberties, such as access to venues otherwise limited to COVID-19-vaccinated individuals.

When joining or becoming a member of the CGC, subscribers are asked to participate in a survey (see Methods). It is the survey findings over the first five months of operation from a specific cohort of subscribers to the CGC that forms the primary subject of this paper.

We, the authors of the present work, are entirely independent of the CGC and have received no funding to undertake it. Since mid-2021, we have collaborated on a diverse range of scientific and medical issues as part of our work with the Health & Humanities Committee (co-chaired by two of the authors: Dr Naseeba Kathrada and Robert Verkerk PhD) of the non-profit World Council for Health (worldcouncilforhealth.org).

METHODS
This survey is based on self-reported data among self-selected individuals from around the world who have subscribed to the CGC ‘control group’ project (vaxcontrolgroup.com). All respondents on which the present analysis is based completed an online survey (see Supplementary Information) on the CGC website on a monthly basis over 5 consecutive months (October 2021 to February 2022 inclusive). This period included the time during which, in most parts of the world, omicron replaced the delta variant as the dominant, circulating variant of SARS-CoV-2. The cohort (n = 18,497) that is the subject of this analysis is a sub-group comprising 6.2% of the 297,618 people who had registered on the website by the end of February 2022 and provided data on a monthly basis over the first 5 consecutive months of the survey. Comparison of findings from this cohort with selected responses from the less complete but entire survey data set of CGC (that includes some 305,000 respondents from around the
world at the time of writing), suggests that this smaller data set is representative of the full
dataset. The online survey includes some initial profile questions (Supplementary Information;
Annex 1) that were answered on registration followed by a further series of questions (Supplementary Information; Annex 2) answered by respondents on a monthly basis thereafter. Recruitment of respondents was entirely organic and relied on respondents being made aware of the CGC project through largely alternative media outlets, given censorship on mainstream media and social media channels. It is important to recognize that because the cohort represents a self-selected, as opposed
to randomly selected, sample, the findings cannot be directly compared with other observational studies based on self-reported data based on randomly selected subjects. However, what the survey aimed to do is gather insights about health outcomes, choices and discrimination experienced by the marginalized sub-population of people from diverse socio-economic backgrounds, ethnicities and cultures who have elected to exercise their right of refusal of COVID-19 injections. As a self-reported survey, the interpretation of results in this paper has focused primarily on providing perspectives on the responses of an unvaccinated population to a variety of factors. Accordingly, central to this ‘look and see’ approach are the proportion of respondents who have given particular responses to the questions provided. ©2022 Alliance for Natural Health International 4 Given not all questions have been answered by all respondents, the denominators for the proportional analyses vary considerably according to how many relevant answers are provided and where these are unexpected, explanation is given in the tables or figures.Some analyses involve just a subset of the respondents (e.g. menstruating, menopausal and post-menopausal women aged 20 to 69) and, again, the denominator is stated.

SURVEY FINDINGS
Characterizing the cohort a. Geographic location The vast majority (98.8%) of non-COVID-19 injected participants were from 6 major continents or regions (Table 1), most being from Europe (40%), with the next larges constituents from Oceania (principally Australia and New Zealand) and North America (USA
and Canada), 27% and 25%, respectively. Table 1. Continental distribution of respondents in cohort.
The geographical distribution of respondents in the self-selected cohort is shown in Fig. 2

Region n %, Africa 171 0.9%; Asia 555 3.0%; Europe 7442 40.2%; North America 4657 25.2%; Oceania 4982 26.9%; South America 576 3.1%; Unknown 114 0.6%; TOTAL (n ) 18383 100.0%

b. Reported age groups and biological sex
The age distribution of the cohort is shown in Figure 3. Overall, of the respondents who disclosed their biological sex (96.3%), 57% of respondents were female and 43% male. The age groups with the greatest numbers of respondents were middle-aged and accordingly would generally be regarded by health authorities as highly susceptible to COVID-19 disease. ©2022 Alliance for Natural Health International 6Figure 3. Age and biological sex distribution of cohort. C. Blood group The blood groups and rhesus factors were reported by 51% of respondents, with expected variations between regions and almost twice as many females rather than males disclosing data (Table 2). Given prevalence of Caucasian ethnicities, the relative order of blood groups (most common to least common) was as expected, as follows: O+ > A+ > O- > B+ > A- > AB+ >B- >AB-

Table 2. Blood group by biological sex of cohort.
Blood group; Female (%); Male (%); Undisclosed biological sex (%) Total
A- 436 (7.0) 182 (5.8) 6 (8.6) 624
A+ 1,778 (28.7) 901 (28.5) 24 (34.3) 2,703
AB- 71 (1.1) 33 (1.0) 0 (0.0) 104
AB+ 265 (4.3) 141 (4.5) 2 (2.9) 408
B- 145 (2.3) 56 (1.8) 0 (0.0) 201
B+ 598 (9.7) 294 (9.3) 5 (7.1) 897
O- 665 (10.7) 359 (11.4) 5 (7.1) 1,029
O+ 2,235 (36.1) 1,196 (37.8) 28 (40.0) 3,459
Total with known blood groups 6193 3162 70 9,425 Rather not Disclose 1,383 1,289 538 3,210
Unknown 2,946 2,842 74 5,862d. Primary reason for not electing to receive COVID-19 ‘vaccine’ Table 3 lists, in descending order of frequency, the most important reasons given by cohort respondents for deciding against COVID-19 injection. Respondents were able to select multiple reasons if they felt them to be of equal importance, hence n = 54,152. Table 3. Frequency among cohort where each reason was reported to be the single most important reason for declining COVID-19 ‘vaccination’.
Reasons for not being covid vaccinated Number of respondents who considered each reason the most
important % Prefer natural medicine interventions 9,084 16.8 Distrust of pharmaceutical interventions 8,896 16.4 Distrust of government information 8,888 16.4 Poor/limited trial study data 8,841 16.3
Fear of long-term adverse reactions 8,348 15.4 Fear of short-term adverse reactions 6,216 11.5
Medical complications 2,376 4.4 Previous vaccine injuries 1,503 2.8 Total 54,152 100.0 ©2022 Alliance for Natural Health International 8 The survey results suggest that five reasons were of almost equal significance (with only 1.4% variance), namely preference for natural medicine interventions, distrust of pharmaceutical companies, distrust of government information, insufficient trial data and concerns over long-term adverse reactions. Only 7% of respondents gave either medical complications or concerns stemming from previous vaccine injuries as the primary reasons for COVID-19 ‘vaccine’ avoidance. e. History of past vaccination Approximately one-third of the cohort reported having been vaccinated as a child, while another one-third reported having not received any vaccine within the last 5 years(Table 4). Table 4. Reported vaccination history for cohort Reported vaccination history N %
As a child 5,405 29.2 In Last 12 months 912 4.9 Less than 5 years ago 2,837 15.3 More than 5 years ago 6,246 33.8Never Vaccinated 782 4.2Rather not Disclose 2,315 12.5 Total 18,497 100.0 The age groups from 20 years through to 84 years had the smallest proportions (2.0- 2.9%) reporting that they had never been vaccinated. Conversely, the youngest age group (ages 0-19 years) reported by far the highest rate of not having received any vaccine (15.9%) (Table 5). Table 5. Reported vaccination history by age group Age group (% in each group) Reported vaccination history 0-19 % 20-49 % 50-64 % 65-84 % 85+ % As a child 494 20.0 1,957 33.5 2,131 30.0 810 26.8 11 17.5 More than 5 years ago 313 12.7 1,956 33.4 2,755 38.8 1,200 39.8 19 30.2 Less than 5 years ago 567 23.0 858 14.7 967 13.6 436 14.4 9 14.3
Rather not Disclose 492 20.0 671 11.5 811 11.4 327 10.8 12 19.0 In Last 12 months 206 8.4 238 4.1 273 3.8 185 6.1 9 4.8Never Vaccinated 392 15.9 170 2.9 157 2.2 60 2.0 3 4.8 Total 2,464 5,850 7,094 3,018 63
Preprint draft, uploaded to ResearchGate June 8, 2022©2022 Alliance for Natural Health International 9. Future vaccination choices Nearly two-thirds of the cohort (64.2%) reported that they would refuse all future vaccines of any type, with about one-fifth (22.5%) choosing to not disclose their choices
(Fig. 4). Only 1.3% reported an interest in receiving flu vaccinations and less than 5% reported that they would receive ‘holiday vaccinations’. The choices were generally similar regardless of age group. Figure 4. Responses to future vaccination choices for all age groups in cohort. g. Willingness to donate blood Around 60% of non-COVID-19 vaccinated respondents, regardless of their blood group indicated their willingness in donating blood, these numbers being approximately three times greater than those unwilling to do so or not disclosing a clear preference one way or another (Fig. 5).
0, 10, 20, 30, 40, 50, 60, 70, 80, 90 ,100
No to All Rather not Disclose Any Non-Trial Vaccinations Holiday Vaccinations Flu Vaccinations
Percentage of respondents ©2022 Alliance for Natural Health International 10 Fig. 5. Percentage of respondents reporting willingness or otherwise to donate blood. Reported outcomes, choices and attitudes a. Respondents who reported COVID-19 during survey period Respondents between the ages of 20 and 49 years reported the greatest incidence of COVID-19 disease (~10-12%), with females consistently reporting slightly more often than males regardless of age group, this likely reflecting the female bias of the cohort. Those aged 70 and over reported the lowest incidence of COVID-19 disease (4.0% females, 3.7% males) (Fig. 6).

Figure 6. Percentage of respondents reporting COVID-19 disease, by age group and biological sex during study period. b. Respondents who reported not experiencing, or at least not being sure of experiencing, COVID-19 disease Over 80% of respondents over the age of 70 and almost 80% between 1 and 19 years were either sure they had not experienced symptomatic COVID-19 disease or were not sure if they had or had not (implying any symptoms were likely to be have been mild and transient). Around three quarters of the age bands between 20 and 49 and 50 to 69 similarly reported no COVID-19 disease (Fig. 7). 0 2 4 6 8 10 12 1-19 20-49 50-69 70+ Percentage of respondents Age category Male Female ©2022 Alliance for Natural Health International 12 Figure 7. Respondents reporting that they had not had COVID-19 disease or were not sure if they had experienced the disease. Additionally, 11.6% of the respondents aged 50 to 69 chose not to disclose their past or current COVID-19 disease status, this choice to not disclose status being considerably lower in other age groups (2.0 – 3.5%). c. Reported COVID-19 antigen testing outcomes Nearly 20% of respondents aged 50 to 69 reported having received one or more positive tests while also experiencing symptoms, with only 1.9% in this same age range reporting positivity in the absence of symptoms (Fig. 8). Those over 70 reported the lowest rate of positive tests, with all age groups reporting much greater rates of positivity with, rather than without, symptoms (Fig. 8). 66 68 70 72 74 76 78 80 82 84 1 to 19 20 to 49 50 to 69 70+ Percentage of respondents % Female % Male Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 13 Figure 8. Percentage of respondents reporting positive antigen tests both with and without COVID-19 symptoms. d. SARS-CoV-2 neutralising antibody outcomes Over 1 in 5 (23.5%) respondents between the ages of 50 and 69 reported having been being positive for SARS-CoV-2 (neutralising) antibodies during the survey period, although only 8.3% of these were confirmed with positive serology tests. Figure 9. Reported positive serology (SARS-CoV-2 neutralising antibodies) by age group. 0 5 10 15 20 25 1-19 20-49 50-69 70+ Percentage of respondents % +ve with symptoms % +ve without symptoms 0 5 10 15 20 25 1-19 20-49 50-69 70+ Percentage of respondents % Confirmed % Unverified ©2022 Alliance for Natural Health International 14 Confirmed or unverified presence of SARS-CoV-2 antibodies were reported least often by the oldest age band, the over 70s, which also had the lowest reported incidence of COVID-19 disease (Fig. 6). e. Reported COVID-19 disease by age group and month The greatest incidence of reported COVID-19 disease was in January 2022, with a clear escalation which mirrors the generalised, global displacement of the dominant circulating SARS-CoV-2 variant from delta to omicron, especially during the European winter (where respondent numbers were greatest) (Fig. 10). Figure 10. Reported COVID-19 disease over 5 months of survey showing proportion in each of four age bands. In terms of age bands, the 50 to 69 years age range reported the highest incidence of COVID-19 disease (12.3% of respondents), followed by the 20 to 49 year group (10.7%), with considerably lower reporting (1.3 -3.8%) of suspected or confirmed COVID-19 disease among both the youngest and oldest age bands (Fig. 11). 0 1 2 3 4 5 6 7 8 9 Oct-21 Nov-21 Dec-21 Jan-22 Feb-22 Perecentage of subjects reporting COVID-19 1-19 20-49 50-69 70+ Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 15 Figure 11. Reported COVID-19 disease by age band during the 5 months of survey. f. Severity of COVID-19 symptoms One quarter (25.1%) of the survey cohort reported some symptomatic disease (n = 4636) at some stage during the survey period, most (~14%) being mild, around 8% reportedly moderate and just 2% with severe disease (Fig. 12). Some 3% reported asymptomatic disease. The 50 to 69 age band reported the highest incidences of disease of all severities (Fig. 12) Figure 12. Reported severity of COVID-19 disease among those with known or suspected SARS-CoV-2 infection as a proportion of the survey cohort. ©2022 Alliance for Natural Health International 16 When patients reporting COVID-19 symptoms were asked for how long they were sick or unwell, of those who answered (n= 4496), 54% indicated they were sick for less than a week, 20% between 1 and 2 weeks and 11% for over 3 weeks (Table 6). Table 6. Reported duration of sickness following suspected or known SARS-CoV-2 infection. Health status n % Generally Well 649 14.4 Sick < 1 Week 2440 54.3 Sick 1-2 Weeks 902 20.1 Sick 3 Weeks+ 505 11.2 Total 4496 100.0 g. Symptoms in relation to age ‘Fatigue’ was the most commonly reported symptom of COVID-19 disease, closely followed by ‘cough’ and ‘muscle or body pain’. Symptom ranking by frequency of reports is shown in Table 7. Table 7. Ranking symptoms by reporting frequency during survey period Symptom Qty Reports Ranking Fatigue 4786 1 Cough 4305 2 Muscle or Body Aches 4296 3 Fever 3613 4 Loss Of Taste 1846 5 Loss Of Smell 1791 6 Difficulty Breathing 1346 7 Diarrhoea 915 8 Most symptoms were reported among the 50 to 69 year age band, with between one and 3 symptoms being most commonly reported in all age classes. In the youngest age class (1-19 years), there were proportionately fewer respondents reporting 4 to 6 symptoms compared with the other three age classes (Fig. 13). Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 17 Figure 13. Number of COVID-19 symptoms reported by age band among those with suspected or known COVID-19 disease. There was relatively little variation in the frequency of reporting of the 8 different symptoms, as shown in Figure 14. 0 200 400 600 800 1000 1200 1-19 20-49 50-69 70+ Number of respondents reporting symptoms Age class No Symptoms Reported 1-3 symptoms 4-6 symptoms 7+ symptoms ©2022 Alliance for Natural Health International 18 Figure 14. Symptoms reported by respondents in 4 age bands with known or suspected COVID-19 disease. h. Reported within-household transmission Over twice (2.2-fold) the number of respondents with suspected or known SARS-CoV-2 infection indicated that other family members within the same household had also suffered COVID-19 disease, compared with those who did not report disease. However, of these, nearly one-third (31%, n = 1435) indicated no other family members in the same household had become ill. i. Hospitalisations Only 74 respondents out of the 5196 (1.4%) who reported suspected or known SARSCoV-2 infection also reported that they were hospitalised following infection. Therefore, outpatient or inpatient hospitalisation was reported in just 0.4% of the full survey cohort. Of these, 15 were outpatient only, another 15 were hospitalised for less than 3 days, 26 were hospitalised between 3 and 7 days, 11 for between 7 and 14 days and only 10 for more than 14 days. 0 10 20 30 40 50 60 Cough Diarrhoea Difficulty Breathing Fatigue Fever Loss Of Smell Loss Of Taste Muscle Or Body Aches Percentage of respondents with reported COVID-19 1-19 20-49 50-69 70+ Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 19 These figures represent an overestimate as in some cases, a single individual made more than one visit to hospital. j. Self-administered treatments among COVID-19 patients The majority of respondents with suspected or confirmed COVID-19 engaged in selfadministered treatments using vitamins (C, D), minerals (zinc) and off-label medications (ivermectin [IVM] and hydroxychloroquine [HCQ]) during the 5-month survey period. Vitamins C, D and zinc were the most common self-administered treatments reported, with some 71% of the survey cohort (n = 3701 out of 5196) reporting regular usage. Selfadministration of these treatments or supportive nutrients was much lower in a hospital setting than at home and declined in frequency as symptom severity increased (Fig. 15). Figure 15. Respondents reporting COVID-19 disease who self-administered vitamins C and D and zinc (=Vit/min), off-label medications (ivermectin [IVM] or hydroxychloroquine [HCQ]) (=IVM/HCQ), or other products or medications (=Other) during the survey period. 0 500 1000 1500 2000 2500 Not hospitalised Hospitalised Not hospitalised Hospitalised Not hospitalised Hospitalised Not hospitalised Hospitalised Generally Well Mild Moderate Severe Number of respondents reporting COVID-19 disease Vit/min IVM / HCQ Other ©2022 Alliance for Natural Health International 20 k. Dietary supplement use among cohort Sixty four percent of all respondents reported taking vitamin C, vitamin D, zinc or quercetin, or any combination of these, routinely during the survey period for preventative purposes (Fig. 16). Among those taking supplements, vitamin D was most commonly consumed (53.3% of respondents), closely followed by vitamin C (51.7%), in turn followed by zinc (42.4%), with quercetin being the least used (15.5%) of the four. Supplement use in North America (USA and Canada) exceeded other parts of the world (Fig. 16). Figure 16. Distribution of CGC respondents routinely taking specific dietary supplements (vitamin C, vitamin D, zinc or quercetin) for prevention. l. Mental health Around 4 in 10 respondents in the survey cohort, regardless of age, reported sustained mild or moderate mental health issues through the duration of the survey. Half this number reported severe mental health issues (Fig. 17). Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 21 Figure 17. Percentage of cohort reporting mild, moderate or severe mental issues during each month of the survey. Over the 5-month survey period, around half the respondents reported sustained mild mental health issues throughout the survey’s duration, the reports being highest for the oldest and youngest age bands. Reports of moderate mental health issues dropped to around 3 to 4 in 10, with reports then being higher among the intermediate age bands. About 2 in 10 in each age band reported severe, sustained mental health issues (Fig. 18). Figure 18. Proportion of respondents reporting mental health issues by age band. 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% Oct-21 Nov-21 Dec-21 Jan-22 Feb-22 Percentage of respondents (n = 18,497) Mild Moderate Severe 0 10 20 30 40 50 60 1 – Mild 2 – Moderate 3 – Severe Percentage of respondents ( n = 18,497) 1-19 20-49 50-69 70+ ©2022 Alliance for Natural Health International 22 m. Bleeding abnormalities There were significant numbers of reports of unusual bleeding among the non-COVID-19 ‘vaccinated’ women in the cohort, particularly those in the age band, representing the highest proportion of menstruating women, ages 20 to 49 (Fig. 19). The most commonly reported named menstrual abnormality was irregular periods (1,210 reports) among the 20 to 49 year age band, this representing 36% of women in the age band. Figure 19. Number of female respondents reporting menstrual or other bleeding abnormalities Additionally, 12.0% of female respondents reported unusual nosebleeds during the course of the survey, compared with 4.7% of men. This difference between females and males was even more pronounced for reports of unspecified unusual bruising, which was reported by 12.7% of females, but just 1.7% of males (all age groups). n. Mask wearing In October and November 2021 (before the omicron variant surge around the world became dominant) there were only slight variations associated with different durations of mask wearing, despite those who never wore masks having the lowest rates of COVID-19 symptom reports. In December 2021 through to February 2022 inclusive, however, there was an apparent 0 200 400 600 800 1000 1200 1400 1600 1800 2000 Heavier BleedingIrregular Periods Longer Bleeding Missed Period Unusual Clotting Other Number of female respondents 1-19 20-49 50-69 70+ Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 23 and clear association between those reporting never wearing a mask and those experiencing the lowest rates of suspected or known COVID-19 disease. These data provide no information on any causal association between mask wearing and COVID-19 disease incidence given the wide range of uncontrolled behavioural and confounding factors likely to be involved. Figure 20. Percentage of respondents with known or suspected COVID-19 disease according to their mask wearing habit over the 5 months of the survey. o. Job losses Job losses among the survey cohort were determined as a proportion of the respondents reporting loss of employment during the survey period, using as the denominator the numbers in the cohort between the ages of 20 and 69 inclusive (the primary working age range) (Fig. 21). The greatest reported job losses in relation to the numbers of respondents in each region were reported in Australia and New Zealand (n = 1,097; 29% of respondents). This rate was over double that reported in North America (n = 467; 13%), and much greater than that from the areas with the next highest losses, namely Southern Europe (n = 73; 13%) and South East Asia (n = 39; 12%). 0 5 10 15 20 Oct-21 Nov-21 Dec-21 Jan-22 Feb-22 Percentage of respondents reporting COVID-19 symptoms % of people with covid disease wearing/not wearing masks > 8 hours Most Days > 4 hours Most Days > 2 hours Most Days Rarely Never ©2022 Alliance for Natural Health International 24 Figure 21. Job losses in different regions among the COVID-19 unvaccinated survey cohort as a proportion of respondents of working age (20 to 69 years). Among the occupations affecting job losses, teachers were the most common, followed by nurses, those declared as self-employed, support workers and social workers. p. Discrimination The survey requested information about whether respondents had faced discrimination personally by members of society, or by their state (country). Between 20% and nearly 50% of respondents, depending on region, reported being personal targets of hate, implying victimisation, owing to their COVID-19 vaccination status (Fig. 22). Proportionately, rates of such victimisation were highest in Southern Europe and South America and lowest in Western Asia and Southern Africa (although the number of respondents in these latter regions were substantially lower). Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 25 Figure 22. Percentage of respondents by region reporting hate or victimisation during the 5-month survey period. Respondents reported feeling even more victimised by their respective states, with rates among respondents being greatest in Southern Europe (61%), Western Europe (59%), Australia and New Zealand (57%) and South America (57%) (Fig. 23). Figure 23. Reported state victimisation of ‘unvaccinated’ respondents. ©2022 Alliance for Natural Health International 26 DISCUSSION As soon as COVID-19 intra-muscular genetic vaccines were issued with emergency use authorisation by national regulatory authorities towards the end of 2020, coercive pressure was placed on populations to receive the injections, starting with the oldest age groups and those deemed most vulnerable to severe COVID-19 disease. These genetic vaccines all utilised either the mRNA (Pfizer, Moderna) or adenoviral vector (e.g. AstraZeneca, Johnson & Johnson, Serum Institute of India, Gamaleya Institute) platform (Heinz and Stiasny, 2021). Large numbers of people in different parts of the world have chosen to avoid the injections. Such dissenters have been widely stigmatised and marginalised by mainstream society, being referred to variously as “anti-vaxxers” or “conspiracy theorists”. At the time of writing, Our World in Data (2022), which consolidates data from official country sources, suggests that 35% of the world population has yet to receive any COVID-19 injections, this number rising to 84% in low-income countries. The same database suggests 77% of the population of the African continent, equating to over 1 billion people, and nearly 31% of Europeans, equating to some 232 million people, have yet to receive any COVID-19 vaccines. Some 22% of Americans (73 million), 14% of Canadians (5.3 million) and 13% of Australians (3.3 million) have reportedly not yet received COVID-19 vaccines (Our World in Data, 2022). The CGC is a grassroots, UK-based, internationally active organisation that came into being in mid-2021 to help support this substantial group of COVID-19 unvaccinated people who had already been subject to victimisation, stigmatisation, discrimination or marginalisation by mainstream society, especially in industrialised countries. By contrast, mainstream society immediately backed, in the absence of robust scientific evidence, global mass vaccination with what were initially experimental products reliant on novel platforms that had never before been tested at scale. CGC respondents in the survey gave various reasons for declining COVID-19 injection, including distrust of health authorities, governments or the pharmaceutical industry, insufficient evidence of safety or effectiveness, or concerns over injuries or potential adverse reactions, for which the manufacturers typically have indemnity in the event of compensation for injuries resulting from vaccination. Since the mass roll-out of experimental products was initiated in late 2020, the products have been found to deliver very little protection against transmission of the current, dominant, circulating, omicron variant (Amanatidou et al, 2022). This means the products do not fulfil the widely accepted purpose of a vaccine, which is to induce herd immunity by triggering an immune response that fully neutralises or sterilises the pathogen so preventing transmission. The World Health Organization (WHO) updated its description of ‘herd immunity’ on 31 December 2020, stating: “WHO supports achieving ‘herd immunity’ through vaccination, not by allowing a disease to spread through any segment of the population, as this would result in unnecessary cases and deaths” (WHO, 2020). Additionally, immunologic effectiveness even against disease was found to wane rapidly, within a few months (Israel et al, 2021; Ferdinands et al, 2022) implying that those relying on COVID-19 injections would Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 27 need to consent to regular, e.g. 6-monthly, exposure to the injections, a regimen that had yet to be subject to any safety trials. There is a growing body of evidence that suggests that individuals reliant on naturallyacquired immunity develop broader-based and more robust immunity to SARS-CoV-2 than those reliant on vaccine-induced immunity (Gazit et al, 2021; Turner et al, 2021; Cohen et al, 2021). Such naturally-acquired immunity is likely to play a key role in dampening the hostpathogen population dynamics of the virus that appears to have been new to humanity prior to 2019, as well as reducing the risk of developing more virulent and transmissible variants (Koyama et al, 2022). Jonathan Pugh and colleagues from the Faculty of Philosophy at the University of Oxford, argued in the Journal of Medical Ethics that “[w]ithout compelling evidence for the superiority of vaccine-induced immunity, it cannot be deemed necessary to require vaccination for those with natural immunity.” (Pugh et al, 2022). It follows that discrimination against individuals who have elected to invoke natural immunity, in place of vaccine-induced immunity, would be unjust. The data from the first 5 months of the CGC survey suggest that unvaccinated populations have not placed any significant additional burden on healthcare systems in their respective countries, as compared with those who consented to COVID-19 injections. In the UK, official data reveals that 33% of the population tested positive via either PCR or lateral flow tests during the whole pandemic, with the highest case rates occurring in late 2021 and early 2022 during the period of the CGC survey (GOV.UK, 2022). While some 25% of CGC survey respondents reported symptomatic COVID-19 disease during the 5 months of the survey, the incidence of disease does not itself indicate the burden on healthcare systems or society; this is better assessed by hospitalization rates and mortality (there were no CGC data available for the latter). The COVID-19 disease burden for the USA was estimated by the US Centers for Disease Control and Prevention (CDC) for the period February 2020 to September 2021 (CDC, 2022). The estimate included 124 million cases of symptomatic illness, 7.5 million hospitalisations and 921,000 deaths. This equates, following a pro rata adjustment to include mean data over a 5-month period to match the survey period of CGC, an average of 10.4% of the US population had symptomatic disease, 0.6% of the US population was hospitalised, and 0.3% died with COVID-19 on their death certificate. By comparison, the self-selected, self-reported, CGC population sample reported 25% symptomatic disease (suspected or confirmed), with just 0.4% of the cohort (one-third less than the adjusted CDC estimate) being hospitalised. The CGC survey did not report on mortality given the self-reporting nature of data collection. While the number in the CGC cohort reported to have experienced symptomatic disease is substantially greater than the CDC figures (25% versus 10.4%), this may be in part because the majority were suspected, rather than confirmed, cases, and so were more likely to have been reported. Cases manifesting as symptomatic disease were greatest among middleaged people in the age band 50 to 69 years, which likely reflects age-dependent ©2022 Alliance for Natural Health International 28 manifestation of disease (Omori et al, 2020), and shielding among the oldest, most vulnerable age group. The adjusted CDC estimates and the CGC survey data should be compared with caution as they originate from different regions of the world, they have been derived from different time periods, the CDC includes different proportions of vaccinated and unvaccinated over the 19 months of its collection, and both datasets relied on different reporting systems. However, it is of interest that the CGC cohort included a period (October 2021 to February 2022 inclusive) with the highest rates of SARS-CoV-2 infection in many parts of the world, including North America and Europe, during the first omicron wave. Overall, the survey findings suggest there is no adequate basis on which to suggest the CGC cohort and, by extension, other health-aware populations who have elected to avoid COVID19 injections, have represented a disproportionate burden on health systems compared with those who have received one or more injections. To the contrary, almost 3 out of 4 respondents who had COVID-19 engaged in self-care using vitamins (D and C), minerals (notably zinc) and/or quercetin. Reported selfadministration of these micronutrients, as well as ivermectin and hydroxychloroquine, dropped off dramatically for those who were hospitalised, presumably at least in part because of lack of support for use of natural products in hospital settings (a phenomenon that has been widely reported to the authors anecdotally). The percentage of populations engaging in preventative self-care using dietary supplements containing vitamins C, D, zinc or quercetin was highest in the USA at 71% of respondents, and somewhat lower, but still high (60-65%), in Europe, Australia and New Zealand. These data compare favourably with the 47% of UK users of the Zoe app in the COVID-19 Symptom Study (n = 372,720) who reported using dietary supplements (Louca et al, 2021). This latter study found modest reductions in risk of infection (9-14%) among those routinely using vitamin D, multivitamins, omega-3 fatty acids or probiotics. Among the most surprising findings in this COVID-19 unvaccinated cohort were the commonly reported instances of menstrual disturbances and bleeding abnormalities in women. Such disturbances have been reported in the literature in association with COVID19 disease (e.g. Sharp et al, 2021), lifestyle changes associated with the pandemic (Bruinvels et al, 2021), and particularly following COVID-19 vaccination (e.g. Alvergne et al, 2021; Trogstad, 2022). The disturbances reported in the survey are likely to be related to COVID19 disease, but other factors such as shedding exposure, chronic stress and changes to lifestyles caused by restrictions and related measures, as well as chronic spike protein exposure (‘spikopathy’) in domestic and occupational settings, could also have been involved. There was a high proportion (around 40%) of respondents who reported mental health issues during the reporting period. This was in line with the effects of ongoing chronic, psychological stress associated with the pandemic, as found in other studies, 66 of which have been pooled as part of a comprehensive, global, systematic review and meta-analysis carried out by a group of Chinese researchers (Wu et al, 2021). Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 29 In this specific cohort that has placed more trust in the human immune system than in novel ‘genetic vaccines’, the mental health burden may be associated more to the human response to the pandemic, rather than psychological, fear-based reactions to any threat posed by the SARS-CoV-2 virus itself. This includes discrimination in the workplace, by peers or by family members, as well as victimisation by states (governments/health authorities) owing to ‘unvaccinated’ status. Much of this disproportionate and discriminatory treatment is likely the result of widespread misunderstandings about, and over-stated benefits of, COVID-19 ‘vaccines’, false claims over societal risks posed by the unvaccinated, media and state propaganda and coercion to ensure high rates of COVID-19 vaccination, institutional mandates, and the desire for in-group identity as explained by social identity theory (Scheepers and Derks, 2016). In line with the scapegoating of those who have not consented to COVID-19 injection, it was also relevant that those respondents in the CGC survey who reported never wearing facial coverings or masks also experienced the lowest incidence of suspected or confirmed COVID19 disease. The scientific basis for the continued pressure on populations to receive COVID-19 ‘vaccines’ and boosters remains elusive. There is still inadequate governmental and health authority recognition of the breadth and depth of injuries which are underreported to the Vaccine Adverse Event Reporting System (VAERS) in the USA (refer to OpenVAERS [www.openvaers.com] for summaries), the Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card system in the UK, EudraVigilance in Europe, and similar national reporting systems elsewhere. Research by a German insurance company, BKK ProVita, suggested in February 2022 following its own analysis of available data, that there is already a “violent alarm signal” in Germany which implies substantial underreporting of injection injuries by the responsible health authority, the Paul Ehrlich Institute. The findings allude that between 4 and 5% of those to whom COVID-19 injections have been administered are engaging, or have engaged, with treatments to deal with COVID-19 injection injuries (Deutsche Wirtschaft Nachricten, 2022), amounting to 2.5 to 3 million people in Germany (Phillips, 2022). Unfortunately, given the desire to uphold the mainstream narrative that wrongly insinuates mass roll-out of COVID-19 vaccines is the only means of resolving the pandemic, the executive responsible for disclosing these findings, Andreas Schöfbeck, was sacked by BKK following public release of the findings (Deutsche Wirtschaft Nachricten, 2022). This is another stark reminder of the discriminatory consequences of speaking out against the mainstream narrative even where ample supporting data are available and in the public interest Similar findings from Israel suggest the scale of COVID-19 injection injuries, and the need for medical support for those affected, is much greater than widely reported (Guetzkow, 2022). ©2022 Alliance for Natural Health International 30 Thus, when comparing health system burdens between COVID-19 vaccinated and ever more constrained unvaccinated (‘control’) populations, the short- and long-term impacts of injection-related injuries needs to be accounted for. There has been a seemingly deliberate effort by vaccine manufacturers and associated Phase 3 clinical trial study teams to remove data that allows comparison of outcomes between COVID-19 injected and un-injected (control) populations. The release of Pfizer data (322 documents at the time of writing) following the successful legal action in the USA by Public Health and Medical Professionals for Transparency (phmpt.org), with which the authors are associated, will likely in time confirm the misleading nature of the safety and effectiveness claims made by health authorities and vaccine manufacturers for the current crop of COVID-19 injections. The findings from the present survey have five main limitations; 1) the respondents are selfselected and therefore not randomly selected; 2) the data are self-reported and therefore have not been verified independently; 3) the ~18,500 participant cohort may have been biased towards the most diligent, health-conscious participants given they all completed monthly surveys (although a number of cross-checks with the main ~300,000 cohort suggests this bias is likely low); 4) there is no available comparative ‘control’ population that includes individuals who have consented to one or more COVID-19 vaccines of different types; and; 5) the questionnaire design is limited and does not account for multiple variables that affect health status, such as socioeconomic status, urban, peri-urban or rural residence, diet, or lifestyle. That being said, the survey data do offer indicative or suggestive evidence that the CGC COVID-19 unvaccinated cohort prioritizes self-care and has placed very little burden on healthcare systems in respective countries. It follows, then, that the marginalization, stigmatization, coercion of and discrimination against this population group, one that has not consented to COVID-19 injections, is neither valid nor ethical. Such discrimination and restriction of liberties based on vaccination status may fall foul of relevant national antidiscrimination laws and international treaties, such as the UN’s International Covenant on Economic, Social and Cultural Rights (ICESCR, 1966), which includes fundamental rights to liberty and security of person, freedom of movement, privacy, religion and belief, freedom of expression, and peaceful assembly. The findings also amplify the great need to ensure that well conducted observational studies are carried out in order to compare outcomes, choices and potential discrimination in COVID-19 vaccinated and unvaccinated populations. ACKNOWLEDGEMENTS Derren Fielder, Diny Fielder-Van Kleef and Rachael Tubbs were responsible for the CGC questionnaire and data collection from respondents. The full CGC dataset was made available to RV who then worked with Derren Fielder to extract selected data for this work. The authors thank Melissa Smith of the Alliance for Natural Health International for helping collate and analyse the data in Excel. Preprint draft, uploaded to ResearchGate June 8, 2022 ©2022 Alliance for Natural Health International 31 DECLARATION OF INTERESTS None of the authors have any competing interests. FUNDING STATEMENT CGC is a membership organization and accordingly receives subscription fees, as well as donations, to help conduct research and provide support for vaccine-free communities as well as COVID-19 vaccinated individuals who have decided to opt out of ongoing vaccination programs.

The authors are entirely independent of CGC and received no funding to undertake the present work.

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Severe COVID ‘Rare’ in People Who Didn’t Get Vaccine, Survey Reveals

A survey of 300,000 people who didn’t get the COVID-19 vaccine revealed the unvaccinated didn’t place a disproportionate burden on health systems — in fact, they experienced very low rates of hospitalization and severe COVID-19.

Authors: Alliance for Natural Health International 06/09/22

There have been very few studies looking at how those who’ve elected to rely on natural immunity and natural products, as compared with those who’ve consented to COVID-19 genetic vaccines, the latter who may or may not have, also tried to optimize their immune systems, fare when it comes to COVID-19.

The few that have been done often mix vaccinated with unvaccinated, as shown in the case of U.K. data by professor Norman Fenton and his group at Queen Mary, University of London.

That changes with the first release of the analysis of survey data from the international Control Group project — also known as the Vax Control Group.

The citizen-led project was initiated by an Eastbourne (U.K.) cooperative, the Control Group Cooperative — and it’s had more than 300,000 subscribers.

Rob Verkerk Ph.D. of Alliance for Natural Health has led a team, including Dr. Naseeba Kathrada (general practitioner, South Africa, Caring Healthcare Workers Coalition), Christof Plothe D.O. (integrative and osteopathic practitioner, Germany) and Dr. Kat Lindley (family physician, USA), that has collated, analyzed and interpreted the first five months of survey data from “control group” participants.

The survey data offer important revelations, including:

  • The unvaccinated “control group” participants don’t place a disproportionate burden on health systems — in fact, quite the opposite, they have experienced very low hospitalization rates and severe COVID-19 disease is rare.
  • They are more likely to self-care, using natural products like vitamin D, vitamin C, zinc and quercetin.
  • Many have used ivermectin and hydroxychloroquine.
  • Women have suffered menstrual and bleeding abnormalities despite being unvaccinated, possibly owing to spike protein exposure and shedding.
  • Their mental health burden has been considerable, possibly aggravated by their stigmatization by the mainstream, “vaccinated” society.
  • They have been heavily discriminated against because of their decision to exercise their right to informed consent and refuse the administration of “genetic vaccines.”

No jab, lower hospitalizations — finds international survey

An international survey of a health-aware, “Control Group” that includes over 300,000 people who have chosen to avoid COVID-19 vaccination, shows participants place minimal burden on health systems through their strong reliance on natural immunity, self-care and the use of natural health supplements to help prevent or even treat COVID-19.

Yet this group faces unfounded discrimination, job losses and mental health issues intensified by its marginalization by mainstream society.

The survey of participants in the “Control Group” includes a sub-group from the over 305,000 participants from more than 175 countries who have joined the citizen-led project and opted to not receive COVID-19 vaccines.

The findings just uploaded to the preprint server ResearchGate, show that during the 5-month survey period (Sept. 2021 through to Feb. 2022 inclusive), participants suffered low rates of severe COVID-19 disease, were infrequently hospitalized, and used natural health products extensively both for prevention and for treatment of mild to moderate COVID-19.

Data from these first five months of the Control Group survey were analyzed and interpreted by an independent, international team led by Robert Verkerk Ph.D., a multi-disciplinary scientist and the founder, executive and scientific director of the non-profit Alliance for Natural Health International.

Co-authors included three practicing clinicians, Dr. Naseeba Kathrada from South Africa, Christof Plothe D.O. from Germany and Dr. Katarina Lindley from the USA.

The authors came together to assess the survey data through their collaboration in recent months with the World Council for Health, a non-profit, global coalition of health-focused organizations and civil society groups.

The survey findings were based on a sub-cohort of approximately 18,500 Control Group participants who had completed questionnaires on a monthly basis over the first five months of the survey.

Among the wide-ranging data collected, the survey captured reasons why participants avoided vaccines, with distrust of governments and pharmaceutical companies as well as concerns over adverse reactions from insufficiently tested vaccines being high on the list.

Participants reported extensive mental health problems that may have been compounded by the stigmatization and discrimination facing those who shunned COVID-19 vaccines.

It also found that women, despite being unvaccinated for COVID-19, suffered menstrual and bleeding abnormalities that may have been associated with viral exposure, shedding, spike protein exposure or pandemic-related behavioral changes. Those who never wore masks reported the lowest levels of COVID-19 disease.

Given the participants are self-selected and have self-reported, the survey findings need to be interpreted with care when comparing them with national statistics or studies based on randomly selected populations.

The U.K.-based Control Group project was established in mid-2021 as a citizen-led cooperative that aims to evaluate long-term health outcomes among the COVID-19 vaccine-free as well as linking its members to country support networks and online community groups.

Mount Sinai researchers develop a rapid test to measure immunity to COVID-19

New blood assay provides critical information for revaccination strategies in vulnerable individuals Peer-Reviewed Publication THE MOUNT SINAI HOSPITAL / MOUNT SINAI SCHOOL OF MEDICINE

Mount Sinai researchers have developed a rapid blood assay that measures the magnitude and duration of someone’s immunity to SARS-CoV-2, the virus that causes COVID-19. This test will allow large-scale monitoring of the population’s immunity and the effectiveness of current vaccines to help design revaccination strategies for vulnerable immunosuppressed individuals, according to a study published in Nature Biotechnology in June.

The test takes less than 24 hours to perform and is scalable to use broadly in the population. It measures the activation of T cells, which are part of our adaptive immune response to SARS-CoV-2 infection or vaccination and help protect against severe disease outcomes or death.

“The assay we have created has the ability to measure the population’s cellular immunity and broadly test the efficacy of novel vaccines,” said one of the study’s senior authors, Ernesto Guccione, PhD, Professor of Oncological Sciences, and Pharmacological Sciences, at The Tisch Cancer Institute at Mount Sinai. “We know that vulnerable populations don’t always mount an antibody response, so measuring T cell activation is critical to assess the full extent of a person’s immunity. Additionally, the emergence of SARS-CoV-2 variants like Omicron, which evade most of the neutralizing ability of antibodies, points to the need for assays that can measure T cells, which are more effective against emerging variants of concern.”

Long-term protection from viral infection is mediated by both antibodies and T cell response. Many recent studies point to the importance of determining T cell function in individuals who have recovered from or been vaccinated against COVID-19 to help design vaccination campaigns. However, before this study, measurement of T cell responses has been rarely performed because of the associated technical challenges.

In conducting this study, Mount Sinai researchers and partners at Duke-NUS Medical School optimized qPCR-based assays that had the potential to be globally scalable, sensitive, and accurate tests. Researchers narrowed their focus to the two assays that offered the most scalability. One, the qTACT assay, was accurate and sensitive but had a relatively longer processing time of 24 hours per 200 blood samples, a moderate price, and a medium level of technical skill. The other, the dqTACT assay, was accurate and had a reduced processing time and cost, and required minimal lab experience, making it easy to implement.

The dqTACT assay has recently been granted the European CE-IVD (in vitro diagnostics) certification, while U.S. Food and Drug Administration and European Medicines Agency clinical validation is ongoing.

“The assays presented here are based on the ability of SARS-CoV-2 T cells to respond to peptides covering different proteins of the virus,” said another senior author, Jordi Ochando, PhD, Assistant Professor of Oncological Sciences at the Tisch Cancer Institute at Mount Sinai and Assistant Professor of Medicine (Nephrology), and Pathology, Molecular, and Cell-Based Medicine at the Icahn School of Medicine at Mount Sinai. “With the possibility of using different peptide pools, our approach represents a flexible strategy that can be easily implemented to detect the presence of T cells responding to different viral proteins. These T cells have an important role in protection from emerging mutant strains, thus immediately gauging the impact that viral mutations might have on cellular immunity.”

Megan Schwarz, a graduate student at Icahn Mount Sinai and first author of the study, added, “Precise measurement of cellular responses underlying virus protection represents a crucial parameter of our levels of immune defense.”

This new study was conducted using laboratory diagnostic services of Synlab and Hyris SystemTM, Hyris’ signature qPCR technology.

At least 58% of U.S. population has natural antibodies from previous Covid infection, CDC says

Authors: Spencer Kimball PUBLISHED TUE, APR 26 2022 CNBC

KEY POINTS

  • Three out of every 5 people in the U.S. now have antibodies from a previous Covid-19 infection, according to a new CDC analysis.
  • The proportion is even higher among children, demonstrating how widespread the virus was during the winter omicron surge.
  • CDC officials told reporters on a call Tuesday that the study did not measure whether people with prior infections had high enough antibody levels to protect against reinfection and severe illness.
  • However, CDC Director Dr. Rochelle Walensky said health officials believe there is a lot of protection against the virus in communities from vaccination, boosting and infection taken together.

Three out of every 5 people in the U.S. now have antibodies from a previous Covid-19 infection with the proportion even higher among children, demonstrating how widespread the virus was during the winter omicron surge, according to data from the Centers for Disease Control and Prevention.

The proportion of people with natural Covid antibodies increased substantially from about 34% of the population in December to about 58% in February during the unprecedent wave of infection driven by the highly contagious omicron variant. The CDC’s analysis didn’t factor in people who had antibodies from vaccination.

The CDC published the data in its Morbidity and Mortality Weekly Report on Tuesday.

The increase in antibody prevalence was most pronounced among children, indicating a high rate of infection among kids during the winter omicron wave. About 75% of children and teenagers now have antibodies from past Covid infections, up from about 45% in December.

The high rate of infection among children is likely due to lower vaccination rates than adults. Only 28% of children 5- to 11-years-old and 59% of teens 12- to 17-years-old were fully vaccinated as of April. Children under 5-years-old are not yet eligible for vaccination.

About 33% of people ages 65 and older, the group with the highest vaccination rate, had antibodies from infection. Roughly 64% of adults ages 18 to 49 and 50% of people 50 to 64 had the antibodies.

The CDC analyzed about 74,000 blood samples every month from September through January from a national commercial lab network. The sample size decreased to about 46,000 in February. The CDC tested the samples for a specific type of antibody that is produced in response to Covid infection, not from vaccination.

CDC officials told reporters on a call Tuesday that the study did not measure whether people with prior infections had high enough antibody levels to protect against reinfection and severe illness. However, CDC Director Dr. Rochelle Walensky said health officials believe there is a lot of protection in communities across the country from vaccination, boosting and infection taken together, while cautioning that vaccination is the safest strategy to protect yourself against the virus.

“Those who have detectable antibody from prior infection, we still continue to encourage them to get vaccinated,” Walensky told reporters during the call. “We don’t know when that infection was. We don’t know whether that protection has waned. We don’t know as much about that level of protection than we do about the protection we get from both vaccines and boosters.”

Scientists in Qatar affiliated with Cornell University found that natural infection provides about 73% protection against hospitalization if a person is reinfected with BA.2. However, three doses of Pfizer’s vaccine provided much higher protection against hospitalization at 98%. The study, published in March, has not undergone peer-review.

About 66% of the U.S. population is fully vaccinated and 77% have received at least one dose, according to data from the CDC.

Infections and hospitalizations have dropped more than 90% from the peak of the omicron wave in January when infections in the U.S. soared to an average of more than 800,000 a day. New cases are rising again due to the BA.2 subvariant. Another subvariant, BA.2.12.1, is now gaining ground in the U.S., representing about 29% of new infections, according to CDC data. Walensky said the public health agency believes BA.2.12.1 spreads about 25% faster than BA.2. However, she said the CDC does not expect to see more severe disease from BA.2.12.1though studies are ongoing.

More than 98% of the U.S. population lives in areas where they do not need to wear masks indoors under CDC guidance due to low Covid community levels, which takes into account both infections and hospitalizations. A U.S. district judge last week struck down the CDC’s mask mandate for public transportation, though the Justice Department has filed an appeal. Walensky said the CDC continues to recommend that people wear masks on public transportation.

Counties With Highest Vaccination Rates See More COVID-19 Cases Than Least Vaccinated

Authors: Petr Svab April 4, 2022 Updated: April 5, 2022 THE EPOCH TIMES

U.S. counties with the highest rates of vaccination against COVID-19 are currently experiencing more cases than those with the lowest vaccination rates, according to data collected by the Centers for Disease Control and Prevention (CDC).

The 500 counties where 62 to 95 percent of the population has been vaccinated detected more than 75 cases per 100,000 residents on average in the past week. Meanwhile, the 500 counties where 11 to 40 percent of the population has been vaccinated averaged about 58 cases per 100,000 residents.

The data is skewed by the fact that the CDC suppresses figures for counties with very low numbers of detected cases (one to nine) for privacy purposes. The Epoch Times calculated the average case rates by assuming the counties with the suppressed numbers had five cases each on average.

The least vaccinated counties tended to be much smaller, averaging less than 20,000 in population. The most vaccinated counties had an average population of over 330,000. More populous counties, however, weren’t more likely to have higher case rates.

Even when comparing counties of similar population, the ones with the most vaccinations tended to have higher case rates than those that reported the least vaccinations.

Among counties with populations of 1 million or more, the 10 most vaccinated had a case rate more than 27 percent higher than the 10 least vaccinated. In counties with populations of 500,000 to 1 million, the 10 most vaccinated had a case rate almost 19 percent higher than the 10 least vaccinated.

In counties with populations of 200,000 to 500,000, the 10 most vaccinated had case rates around 55 percent higher than the 10 least vaccinated.

The difference was more than 200 percent for counties with populations of 100,000 to 200,000.

For counties with smaller populations, the comparison becomes increasingly difficult because so much of the data is suppressed.

Another problem is that the prevalence of testing for COVID-19 infections isn’t uniform. A county may have a low case number on paper because its residents are tested less often.

The massive spike in infections during the winter appears to have abated in recent weeks. Detected infections are down to less than 30,000 per day from a high of over 800,000 per day in mid-January, according to CDC data. The seven-day average of currently hospitalized dropped to about 11,000 on April 1, from nearly 150,000 in January.

The most recent wave of COVID-19 has been attributed to the Omicron virus variant, which is more transmissible but less virulent. The variant also seems more capable of overcoming any protection offered by the vaccines, though, according to the CDC, the vaccines still reduce the risk of severe disease.

Never Had Covid? You May Hold KeyTo Beating the Virus

Authors: Madison Muller 02:30 PM IST, 30 Mar 2022 06:48 PM IST, 30 Mar 2022 Read more at:  https://www.bloombergquint.com/onweb/never-had-covid-you-may-hold-key-to-beating-the-virus
Copyright © Bloomberg

More than half of Americans may have never had Covid, according to U.S. government data, leaving scientists wondering whether those who’ve avoided the novel coronavirus might actually be immune to the virus altogether. This could offer new clues into how to attack Covid. At this stage in the pandemic, people may be immune due to vaccines, a past infection, or a combination of both. There’s also evidence that, in rare instances, some people may be Covid-immune without infection or vaccination at all.

The coronavirus’s frequent mutations and the fact that immunity wanes over time make it difficult to discern how many people are immune at any given moment.  Studies have shown, for example, that while omicron infections offer some immunity against delta, omicron is able to circumvent antibodies from both past infection with other variants and vaccination. Current surveillance techniques have also likely vastly underestimated the number of cases, as more people are taking Covid tests at home and not reporting the results. 

“It’s nearly impossible to gauge protection,” said Andy Pekosz, a virologist at Johns Hopkins Bloomberg School of Public Health.

As cases yet again rise in many regions more than two years into the pandemic, studying those who have not yet caught Covid has become just as critical as studying those who have. Experts say that people with so-called “super” immunity who appear resistant to the virus without vaccination may hold answers to important questions about why certain people get so sick while others don’t. Examining these cases could also help inform the development of vaccines and therapeutics less vulnerable to viral mutations.

“It is essentially defining what a best-case scenario looks like, which can also help to identify what is going wrong in those that don’t control the virus,” said Leo Swadling, an immunologist at the University College of London. 

It may be hard to believe that at this stage of the pandemic so many people have still never gotten sick. Perhaps people were asymptomatic and never knew they were infected, or, despite exposure to the virus, they just never tested positive. But even half of the population getting Covid is actually an extraordinary number of infections. The 1918 Spanish flu is estimated to have only infected 25% of the U.S. population at the time, despite causing a huge number of deaths.

Early in the pandemic, Swadling set out to find out more about the lucky few who weren’t getting sick.

“We were particularly interested in people who are exposed to the virus, but control it very quickly, clearing the virus before it can replicate to detectable levels and before it induces an antibody response,” Swadling said. “It may help us better understand what immunity is best at protection from reinfection.”

Swadling, along with colleagues in London, published a study in the journal Nature last November evaluating a group of U.K. health care workers during the first wave of the pandemic. They found evidence that some of the health care workers exposed to the virus were able to rid their bodies of it even before producing Covid-specific antibodies.

It turned out that for those people, exposure to other human coronaviruses, such as those that cause cold-like symptoms, had helped their bodies to fight off the novel coronavirus. This is because T-cells, a critical part of the body’s immune response, were able to recognize and target genetic elements of prior seasonal coronaviruses that also happened to be present in SARS-CoV-2.  That meant their bodies were able to attack the novel virus without the production of new antibodies specific to it.

Notably, the T-cells that those health care workers produced targeted a different part of the virus than the T-cells did in people who have a detectable Covid infection. Swadling said the while the T-cells produced by both vaccines and a detectable Covid-19 infection attack the frequently mutating spike protein of a virus, these health care workers’ T-cells instead targeted the virus’ internal machinery. Researchers call these T-cells that appear effective against different coronaviruses  “cross-reactive.”

“We identified new parts of the virus that we can put into a vaccine to try to improve it ,” Swadling said. These improvements, he said, could make vaccines better at preventing infection, more effective against new variants and more protective for immunocompromised individuals.

Immunity to a virus occurs when the body is able to recognize a pathogen and effectively fend off infection or disease. Antibodies, such as those acquired from a vaccine or previous infection, attack a virus as soon as it enters the body. T-cells act as another line of defense, working to stop the spread of infection and development of disease once the virus has made it into the body. The mRNA vaccines such as those made by Pfizer and Moderna work by training the body to safely produce antibodies without infection, but they also spur the production of T-cells and B-cells. That’s why the vaccines effectively prevent hospitalization even when they don’t prevent infection altogether — even when antibodies have waned, T-cells are still there to help fight off an infection more quickly.

The study’s authors proposed that T-cells they found— the ones that target the virus’ internal machinery— may offer better protection against emerging variants because of their ability to attack a key part of the virus less vulnerable to mutations than its spike protein. They theorize that targeting those areas of the virus could make the shots more effective.

As labs work to develop a single shot that would offer broader protection against any Covid variant, at least one company, Gritstone Bio Inc., is looking to put Swadling’s theories to the test. Others have reached similar conclusions as Swadling and his colleagues. One study found that in households where some people remained Covid-free despite exposure, those people also appeared protected by T-cells from past exposure to coronaviruses. Another study from January found that some children who did not develop Covid antibodies also had cross-reactive T-cells, which may be part of the reason why children generally have milder symptoms.

Knowing how many people have this heightened immune response is extremely difficult to assess. Some people may have managed to avoid the virus through continued caution or simply luck. But perhaps more important than knowing how many people fall into this category is the information about immunity that can be gathered from studying what sets them apart.

 “T-cells are very long-lived so we may not need repeated vaccination,” Swadling said. 

Studying the super-immune, he said, may help us against omicron — and any future variants of concern.

Read more at: https://www.bloombergquint.com/onweb/never-had-covid-you-may-hold-key-to-beating-the-virus
Copyright © BloombergQuint

SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans

Authors: Jackson S. TurnerWooseob KimElizaveta KalaidinaCharles W. GossAdriana M. RauseoAaron J. SchmitzLena HansenAlem HaileMichael K. KlebertIskra PusicJane A. O’HalloranRachel M. Presti & Ali H. Ellebedy 

Nature volume 595, pages421–425 (2021)

Abstract

Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies1,2,3,4,5,6,7. Individuals who have recovered from COVID-19 have a substantially lower risk of reinfection with SARS-CoV-28,9,10. Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived11,12,13. Here we show that in convalescent individuals who had experienced mild SARS-CoV-2 infections (n = 77), levels of serum anti-SARS-CoV-2 spike protein (S) antibodies declined rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. We show that S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory B cells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.

Main

Reinfections by seasonal coronaviruses occur 6 to 12 months after the previous infection, indicating that protective immunity against these viruses may be short-lived14,15. Early reports documenting rapidly declining antibody titres in the first few months after infection in individuals who had recovered from COVID-19 suggested that protective immunity against SARS-CoV-2 might be similarly transient11,12,13. It was also suggested that infection with SARS-CoV-2 could fail to elicit a functional germinal centre response, which would interfere with the generation of long-lived plasma cells3,4,5,7,16. More recent reports analysing samples that were collected approximately 4 to 6 months after infection indicate that SARS-CoV-2 antibody titres decline more slowly than in the initial months after infection8,17,18,19,20,21. Durable serum antibody titres are maintained by long-lived plasma cells—non-replicating, antigen-specific plasma cells that are detected in the bone marrow long after the clearance of the antigen1,2,3,4,5,6,7. We sought to determine whether they were detectable in convalescent individuals approximately 7 months after SARS-CoV-2 infection.

Biphasic decay of anti-S antibody titres

Blood samples were collected approximately 1 month after the onset of symptoms from 77 individuals who were convalescing from COVID-19 (49% female, 51% male, median age 49 years), the majority of whom had experienced mild illness (7.8% hospitalized, Extended Data Tables 12). Follow-up blood samples were collected three times at approximately three-month intervals. Twelve convalescent participants received either the BNT162b2 (Pfizer) or the mRNA-1273 (Moderna) SARS-CoV-2 vaccine between the last two time points; these post-vaccination samples were not included in our analyses. In addition, bone marrow aspirates were collected from 18 of the convalescent individuals at 7 to 8 months after infection and from 11 healthy volunteers with no history of SARS-CoV-2 infection or vaccination. Follow-up bone marrow aspirates were collected from 5 of the 18 convalescent individuals and from 1 additional convalescent donor approximately 11 months after infection (Fig. 1a, Extended Data Tables 34). We first performed a longitudinal analysis of circulating anti-SARS-CoV-2 serum antibodies. Whereas anti-SARS-CoV-2 spike protein (S) IgG antibodies were undetectable in blood from control individuals, 74 out of the 77 convalescent individuals had detectable serum titres approximately 1 month after the onset of symptoms. Between 1 and 4 months after symptom onset, overall anti-S IgG titres decreased from a mean loge-transformed half-maximal dilution of 6.3 to 5.7 (mean difference 0.59 ± 0.06, P < 0.001). However, in the interval between 4 and 11 months after symptom onset, the rate of decline slowed, and mean titres decreased from 5.7 to 5.3 (mean difference 0.44 ± 0.10, P < 0.001; Fig. 1a). In contrast to the anti-S antibody titres, IgG titres against the 2019–2020 inactivated seasonal influenza virus vaccine were detected in all control individuals and individuals who were convalescing from COVID-19, and declined much more gradually, if at all over the course of the study, with mean titres decreasing from 8.0 to 7.9 (mean difference 0.16 ± 0.06, P = 0.042) and 7.9 to 7.8 (mean difference 0.02 ± 0.08, P = 0.997) across the 1-to-4-month and 4-to-11-month intervals after symptom onset, respectively (Fig. 1b).

figure 1
Fig. 1: SARS-CoV-2 infection elicits durable serum anti-S antibody titres.

Induction of S-binding long-lived BMPCs

The relatively rapid early decline in the levels of anti-S IgG, followed by a slower decrease, is consistent with a transition from serum antibodies being secreted by short-lived plasmablasts to secretion by a smaller but more persistent population of long-lived plasma cells generated later in the immune response. The majority of this latter population resides in the bone marrow1,2,3,4,5,6. To investigate whether individuals who had recovered from COVID-19 developed a virus-specific long-lived BMPC compartment, we examined bone marrow aspirates obtained approximately 7 and 11 months after infection for anti-SARS-CoV-2 S-specific BMPCs. We magnetically enriched BMPCs from the aspirates and then quantified the frequencies of those secreting IgG and IgA directed against the 2019–2020 influenza virus vaccine, the tetanus–diphtheria vaccine and SARS-CoV-2 S by enzyme-linked immunosorbent spot assay (ELISpot) (Fig. 2a). Frequencies of influenza- and tetanus–diphtheria-vaccine-specific BMPCs were comparable between control individuals and convalescent individuals. IgG- and IgA-secreting S-specific BMPCs were detected in 15 and 9 of the 19 convalescent individuals, respectively, but not in any of the 11 control individuals (Fig. 2b). Notably, none of the control individuals or convalescent individuals had detectable S-specific antibody-secreting cells in the blood at the time of bone marrow sampling, indicating that the detected BMPCs represent bone-marrow-resident cells and not contamination from circulating plasmablasts. Frequencies of anti-S IgG BMPCs were stable among the 5 convalescent individuals who were sampled a second time approximately 4 months later, and frequencies of anti-S IgA BMPCs were stable in 4 of these 5 individuals but had decreased to below the limit of detection in one individual (Fig. 2c). Consistent with their stable BMPC frequencies, anti-S IgG titres in the 5 convalescent individuals remained consistent between 7 and 11 months after symptom onset. IgG titres measured against the receptor-binding domain (RBD) of the S protein—a primary target of neutralizing antibodies—were detected in 4 of the 5 convalescent individuals and were also stable between 7 and 11 months after symptom onset (Fig. 2d). Frequencies of anti-S IgG BMPCs showed a modest but significant correlation with circulating anti-S IgG titres at 7–8 months after the onset of symptoms in convalescent individuals, consistent with the long-term maintenance of antibody levels by these cells (r = 0.48, P = 0.046). In accordance with previous reports22,23,24, frequencies of influenza-vaccine-specific IgG BMPCs and antibody titres exhibited a strong and significant correlation (r = 0.67, P < 0.001; Fig. 2e). Nine of the aspirates from control individuals and 12 of the 18 aspirates that were collected 7 months after symptom onset from convalescent individuals yielded a sufficient number of BMPCs for additional analysis by flow cytometry. We stained these samples intracellularly with fluorescently labelled S and influenza virus haemagglutinin (HA) probes to identify and characterize antigen-specific BMPCs. As controls, we also intracellularly stained peripheral blood mononuclear cells (PBMCs) from healthy volunteers one week after vaccination against SARS-CoV-2 or seasonal influenza virus (Fig. 3a, Extended Data Fig. 1a–c). Consistent with the ELISpot data, low frequencies of S-binding BMPCs were detected in 10 of the 12 samples from convalescent individuals, but not in any of the 9 control samples (Fig. 3b). Although both recently generated circulating plasmablasts and S- and HA-binding BMPCs expressed BLIMP-1, the BMPCs were differentiated by their lack of expression of Ki-67—indicating a quiescent state—as well as by higher levels of CD38 (Fig. 3c).

figure 2
Fig. 2: SARS-CoV-2 infection elicits S-binding long-lived BMPCs.
figure 3
Fig. 3: SARS-CoV-2 S-binding BMPCs are quiescent and distinct from circulating plasmablasts.

Robust S-binding memory B cell response

Memory B cells form the second arm of humoral immune memory. After re-exposure to an antigen, memory B cells rapidly expand and differentiate into antibody-secreting plasmablasts. We examined the frequency of SARS-CoV-2-specific circulating memory B cells in individuals who were convalescing from COVID-19 and in healthy control individuals. We stained PBMCs with fluorescently labelled S probes and determined the frequency of S-binding memory B cells among isotype-switched IgDloCD20+ memory B cells by flow cytometry. For comparison, we co-stained the cells with fluorescently labelled influenza virus HA probes (Fig. 4a, Extended Data Fig. 1d). S-binding memory B cells were identified in convalescent individuals in the first sample that was collected approximately one month after the onset of symptoms, with comparable frequencies to influenza HA-binding memory B cells (Fig. 4b). S-binding memory B cells were maintained for at least 7 months after symptom onset and were present at significantly higher frequencies relative to healthy controls—comparable to the frequencies of influenza HA-binding memory B cells that were identified in both groups (Fig. 4c).

figure 4
Fig. 4: SARS-CoV-2 infection elicits a robust memory B cell response.

Discussion

This study sought to determine whether infection with SARS-CoV-2 induces antigen-specific long-lived BMPCs in humans. We detected SARS-CoV-2 S-specific BMPCs in bone marrow aspirates from 15 out of 19 convalescent individuals, and in none from the 11 control participants. The frequencies of anti-S IgG BMPCs modestly correlated with serum IgG titres at 7–8 months after infection. Phenotypic analysis by flow cytometry showed that S-binding BMPCs were quiescent, and their frequencies were largely consistent in 5 paired aspirates collected at 7 and 11 months after symptom onset. Notably, we detected no S-binding cells among plasmablasts in blood samples collected at the same time as the bone marrow aspirates by ELISpot or flow cytometry in any of the convalescent or control samples. Together, these data indicate that mild SARS-CoV-2 infection induces a long-lived BMPC response. In addition, we showed that S-binding memory B cells in the blood of individuals who had recovered from COVID-19 were present at similar frequencies to those directed against influenza virus HA. Overall, our results are consistent with SARS-CoV-2 infection eliciting a canonical T-cell-dependent B cell response, in which an early transient burst of extrafollicular plasmablasts generates a wave of serum antibodies that decline relatively quickly. This is followed by more stably maintained levels of serum antibodies that are supported by long-lived BMPCs.

Although this overall trend captures the serum antibody dynamics of the majority of participants, we observed that in three participants, anti-S serum antibody titres increased between 4 and 7 months after the onset of symptoms, after having initially declined between 1 and 4 months. This could be stochastic noise, could represent increased net binding affinity as early plasmablast-derived antibodies are replaced by those from affinity-matured BMPCs, or could represent increases in antibody concentration from re-encounter with the virus (although none of the participants in our cohort tested positive a second time). Although anti-S IgG titres in the convalescent cohort were relatively stable in the interval between 4 and 11 months after symptom onset, they did measurably decrease, in contrast to anti-influenza virus vaccine titres. It is possible that this decline reflects a final waning of early plasmablast-derived antibodies. It is also possible that the lack of decline in influenza titres was due to boosting through exposure to influenza antigens. Our data suggest that SARS-CoV-2 infection induces a germinal centre response in humans because long-lived BMPCs are thought to be predominantly germinal-centre-derived7. This is consistent with a recent study that reported increased levels of somatic hypermutation in memory B cells that target the RBD of SARS-CoV-2 S in convalescent individuals at 6 months compared to 1 month after infection20.

To our knowledge, the current study provides the first direct evidence for the induction of antigen-specific BMPCs after a viral infection in humans. However, we do acknowledge several limitations. Although we detected anti-S IgG antibodies in serum at least 7 months after infection in all 19 of the convalescent donors from whom we obtained bone marrow aspirates, we failed to detect S-specific BMPCs in 4 donors. Serum anti-S antibody titres in those four donors were low, suggesting that S-specific BMPCs may potentially be present at very low frequencies that are below the limit of detection of the assay. Another limitation is that we do not know the fraction of the S-binding BMPCs detected in our study that encodes neutralizing antibodies. SARS-CoV-2 S protein is the main target of neutralizing antibodies17,25,26,27,28,29,30 and a correlation between serum anti-S IgG binding and neutralization titres has been documented17,31. Further studies will be required to determine the epitopes that are targeted by BMPCs and memory B cells, as well as their clonal relatedness. Finally, although our data document a robust induction of long-lived BMPCs after infection with SARS-CoV-2, it is critical to note that our convalescent individuals mostly experienced mild infections. Our data are consistent with a report showing that individuals who recovered rapidly from symptomatic SARS-CoV-2 infection generated a robust humoral immune response32. It is possible that more-severe SARS-CoV-2 infections could lead to a different outcome with respect to long-lived BMPC frequencies, owing to dysregulated humoral immune responses. This, however, has not been the case in survivors of the 2014 Ebola virus outbreak in West Africa, in whom severe viral infection induced long-lasting antigen-specific serum IgG antibodies33.

Long-lived BMPCs provide the host with a persistent source of preformed protective antibodies and are therefore needed to maintain durable immune protection. However, the longevity of serum anti-S IgG antibodies is not the only determinant of how durable immune-mediated protection will be. Isotype-switched memory B cells can rapidly differentiate into antibody-secreting cells after re-exposure to a pathogen, offering a second line of defence34. Encouragingly, the frequency of S-binding circulating memory B cells at 7 months after infection was similar to that of B cells directed against contemporary influenza HA antigens. Overall, our data provide strong evidence that SARS-CoV-2 infection in humans robustly establishes the two arms of humoral immune memory: long-lived BMPCs and memory B cells. These findings provide an immunogenicity benchmark for SARS-CoV-2 vaccines and a foundation for assessing the durability of primary humoral immune responses that are induced in humans after viral infections.

Methods

Data reporting

No statistical methods were used to predetermine sample size. The experiments were not randomized and the investigators were not blinded during outcome assessment.

Sample collection, preparation and storage

All studies were approved by the Institutional Review Board of Washington University in St Louis. Written consent was obtained from all participants. Seventy-seven participants who had recovered from SARS-CoV-2 infection and eleven control individuals without a history of SARS-CoV-2 infection were enrolled (Extended Data Tables 14). Blood samples were collected in EDTA tubes and PBMCs were enriched by density gradient centrifugation over Ficoll 1077 (GE) or Lymphopure (BioLegend). The remaining red blood cells were lysed with ammonium chloride lysis buffer, and cells were immediately used or cryopreserved in 10% dimethyl sulfoxide in fetal bovine serum (FBS). Bone marrow aspirates of approximately 30 ml were collected in EDTA tubes from the iliac crest of 18 individuals who had recovered from COVID-19 and the control individuals. Bone marrow mononuclear cells were enriched by density gradient centrifugation over Ficoll 1077, and the remaining red blood cells were lysed with ammonium chloride buffer (Lonza) and washed with phosphate-buffered saline (PBS) supplemented with 2% FBS and 2 mM EDTA. Bone marrow plasma cells were enriched from bone marrow mononuclear cells using the CD138 Positive Selection Kit II (Stemcell) and immediately used for ELISpot or cryopreserved in 10% dimethyl sulfoxide in FBS.

Antigens

Recombinant soluble spike protein (S) and its receptor-binding domain (RBD) derived from SARS-CoV-2 were expressed as previously described35. In brief, mammalian cell codon-optimized nucleotide sequences coding for the soluble version of S (GenBank: MN908947.3, amino acids (aa) 1–1,213) including a C-terminal thrombin cleavage site, T4 foldon trimerization domain and hexahistidine tag cloned into the mammalian expression vector pCAGGS. The S protein sequence was modified to remove the polybasic cleavage site (RRAR to A) and two stabilizing mutations were introduced (K986P and V987P, wild-type numbering). The RBD, along with the signal peptide (aa 1–14) plus a hexahistidine tag were cloned into the mammalian expression vector pCAGGS. Recombinant proteins were produced in Expi293F cells (Thermo Fisher Scientific) by transfection with purified DNA using the ExpiFectamine 293 Transfection Kit (Thermo Fisher Scientific). Supernatants from transfected cells were collected 3 (for S) or 4 (for RBD) days after transfection, and recombinant proteins were purified using Ni-NTA agarose (Thermo Fisher Scientific), then buffer-exchanged into PBS and concentrated using Amicon Ultracel centrifugal filters (EMD Millipore). For flow cytometry staining, recombinant S was labelled with Alexa Fluor 647- or DyLight 488-NHS ester (Thermo Fisher Scientific); excess Alexa Fluor 647 and DyLight 488 were removed using 7-kDa and 40-kDa Zeba desalting columns, respectively (Pierce). Recombinant HA from A/Michigan/45/2015 (aa 18–529, Immune Technology) was labelled with DyLight 405-NHS ester (Thermo Fisher Scientific); excess DyLight 405 was removed using 7-kDa Zeba desalting columns. Recombinant HA from A/Brisbane/02/2018 (aa 18–529) and B/Colorado/06/2017 (aa 18–546) (both Immune Technology) were biotinylated using the EZ-Link Micro NHS-PEG4-Biotinylation Kit (Thermo Fisher Scientific); excess biotin was removed using 7-kDa Zeba desalting columns.

ELISpot

Plates were coated with Flucelvax Quadrivalent 2019/2020 seasonal influenza virus vaccine (Sequiris), tetanus–diphtheria vaccine (Grifols), recombinant S or anti-human Ig. Direct ex vivo ELISpot was performed to determine the number of total, vaccine-binding or recombinant S-binding IgG- and IgA-secreting cells present in BMPC and PBMC samples using IgG/IgA double-colour ELISpot Kits (Cellular Technology) according to the manufacturer’s instructions. ELISpot plates were analysed using an ELISpot counter (Cellular Technology).

ELISA

Assays were performed in 96-well plates (MaxiSorp, Thermo Fisher Scientific) coated with 100 μl of Flucelvax 2019/2020 or recombinant S in PBS, and plates were incubated at 4 °C overnight. Plates were then blocked with 10% FBS and 0.05% Tween-20 in PBS. Serum or plasma were serially diluted in blocking buffer and added to the plates. Plates were incubated for 90 min at room temperature and then washed 3 times with 0.05% Tween-20 in PBS. Goat anti-human IgG–HRP (Jackson ImmunoResearch, 1:2,500) was diluted in blocking buffer before adding to wells and incubating for 60 min at room temperature. Plates were washed 3 times with 0.05% Tween-20 in PBS, and then washed 3 times with PBS before the addition of o-phenylenediamine dihydrochloride peroxidase substrate (Sigma-Aldrich). Reactions were stopped by the addition of 1 M HCl. Optical density measurements were taken at 490 nm. The half-maximal binding dilution for each serum or plasma sample was calculated using nonlinear regression (GraphPad Prism v.8). The limit of detection was defined as 1:30.

Statistics

Spearman’s correlation coefficients were estimated to assess the relationship between 7-month anti-S and anti-influenza virus vaccine IgG titres and the frequencies of BMPCs secreting IgG specific for S and for influenza virus vaccine, respectively. Means and pairwise differences of antibody titres at each time point were estimated using a linear mixed model analysis with a first-order autoregressive covariance structure. Time since symptom onset was treated as a categorical fixed effect for the 4 different sample time points spaced approximately 3 months apart. P values were adjusted for multiple comparisons using Tukey’s method. All analyses were conducted using SAS v.9.4 (SAS Institute) and Prism v.8.4 (GraphPad), and P values of less than 0.05 were considered significant.

Flow cytometry

Staining for flow cytometry analysis was performed using cryo-preserved magnetically enriched BMPCs and cryo-preserved PBMCs. For BMPC staining, cells were stained for 30 min on ice with CD45-A532 (HI30, Thermo Fisher Scientific, 1:50), CD38-BB700 (HIT2, BD Horizon, 1:500), CD19-PE (HIB19, 1:200), CXCR5-PE-Dazzle 594 (J252D4, 1:50), CD71-PE-Cy7 (CY1G4, 1:400), CD20-APC-Fire750 (2H7, 1:400), CD3-APC-Fire810 (SK7, 1:50) and Zombie Aqua (all BioLegend) diluted in Brilliant Stain buffer (BD Horizon). Cells were washed twice with 2% FBS and 2 mM EDTA in PBS (P2), fixed for 1 h using the True Nuclear permeabilization kit (BioLegend), washed twice with perm/wash buffer, stained for 1h with DyLight 405-conjugated recombinant HA from A/Michigan/45/2015, DyLight 488- and Alexa 647-conjugated S, Ki-67-BV711 (Ki-67, 1:200, BioLegend) and BLIMP-1-A700 (646702, 1:50, R&D), washed twice with perm/wash buffer, and resuspended in P2. For memory B cell staining, PBMCs were stained for 30 min on ice with biotinylated recombinant HAs diluted in P2, washed twice, then stained for 30 min on ice with Alexa 647-conjugated S, IgA-FITC (M24A, Millipore, 1:500), IgG-BV480 (goat polyclonal, Jackson ImmunoResearch, 1:100), IgD-SB702 (IA6-2, Thermo Fisher Scientific, 1:50), CD38-BB700 (HIT2, BD Horizon, 1:500), CD20-Pacific Blue (2H7, 1:400), CD4-BV570 (OKT4, 1:50), CD24-BV605 (ML5, 1:100), streptavidin-BV650, CD19-BV750 (HIB19, 1:100), CD71-PE (CY1G4, 1:400), CXCR5-PE-Dazzle 594 (J252D4, 1:50), CD27-PE-Cy7 (O323, 1:200), IgM-APC-Fire750 (MHM-88, 1:100), CD3-APC-Fire810 (SK7, 1:50) and Zombie NIR (all BioLegend) diluted in Brilliant Stain buffer (BD Horizon), and washed twice with P2. Cells were acquired on an Aurora using SpectroFlo v.2.2 (Cytek). Flow cytometry data were analysed using FlowJo v.10 (Treestar). In each experiment, PBMCs were included from convalescent individuals and control individuals.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this paper.

Data availability

Relevant data are available from the corresponding author upon reasonable request.

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COVID-19 Cases and Hospitalizations by COVID-19 Vaccination Status and Previous COVID-19 Diagnosis — California and New York, May–November 2021

Weekly / January 28, 2022 / 71(4);125–131 January 19, 2022, this report was posted online as an MMWR Early Release.

Authors: Tomás M. León, PhD1; Vajeera Dorabawila, PhD2; Lauren Nelson, MPH1; Emily Lutterloh, MD2,3; Ursula E. Bauer, PhD2; Bryon Backenson, MPH2,3; Mary T. Bassett, MD2; Hannah Henry, MPH1; Brooke Bregman, MPH1; Claire M. Midgley, PhD4; Jennifer F. Myers, MPH1; Ian D. Plumb, MBBS4; Heather E. Reese, PhD4; Rui Zhao, MPH1; Melissa Briggs-Hagen, MD4; Dina Hoefer, PhD2; James P. Watt, MD1; Benjamin J. Silk, PhD4; Seema Jain, MD1; Eli S. Rosenberg, PhD2,3

Summary

What is already known about this topic?

Data are limited regarding the risks for SARS-CoV-2 infection and hospitalization after COVID-19 vaccination and previous infection.

What is added by this report?

During May–November 2021, case and hospitalization rates were highest among persons who were unvaccinated without a previous diagnosis. Before Delta became the predominant variant in June, case rates were higher among persons who survived a previous infection than persons who were vaccinated alone. By early October, persons who survived a previous infection had lower case rates than persons who were vaccinated alone.

What are the implications for public health practice?

Although the epidemiology of COVID-19 might change as new variants emerge, vaccination remains the safest strategy for averting future SARS-CoV-2 infections, hospitalizations, long-term sequelae, and death. Primary vaccination, additional doses, and booster doses are recommended for all eligible persons. Additional future recommendations for vaccine doses might be warranted as the virus and immunity levels change.

By November 30, 2021, approximately 130,781 COVID-19–associated deaths, one in six of all U.S. deaths from COVID-19, had occurred in California and New York.* COVID-19 vaccination protects against infection with SARS-CoV-2 (the virus that causes COVID-19), associated severe illness, and death (1,2); among those who survive, previous SARS-CoV-2 infection also confers protection against severe outcomes in the event of reinfection (3,4). The relative magnitude and duration of infection- and vaccine-derived protection, alone and together, can guide public health planning and epidemic forecasting. To examine the impact of primary COVID-19 vaccination and previous SARS-CoV-2 infection on COVID-19 incidence and hospitalization rates, statewide testing, surveillance, and COVID-19 immunization data from California and New York (which account for 18% of the U.S. population) were analyzed. Four cohorts of adults aged ≥18 years were considered: persons who were 1) unvaccinated with no previous laboratory-confirmed COVID-19 diagnosis, 2) vaccinated (14 days after completion of a primary COVID-19 vaccination series) with no previous COVID-19 diagnosis, 3) unvaccinated with a previous COVID-19 diagnosis, and 4) vaccinated with a previous COVID-19 diagnosis. Age-adjusted hazard rates of incident laboratory-confirmed COVID-19 cases in both states were compared among cohorts, and in California, hospitalizations during May 30–November 20, 2021, were also compared. During the study period, COVID-19 incidence in both states was highest among unvaccinated persons without a previous COVID-19 diagnosis compared with that among the other three groups. During the week beginning May 30, 2021, compared with COVID-19 case rates among unvaccinated persons without a previous COVID-19 diagnosis, COVID-19 case rates were 19.9-fold (California) and 18.4-fold (New York) lower among vaccinated persons without a previous diagnosis; 7.2-fold (California) and 9.9-fold lower (New York) among unvaccinated persons with a previous COVID-19 diagnosis; and 9.6-fold (California) and 8.5-fold lower (New York) among vaccinated persons with a previous COVID-19 diagnosis. During the same period, compared with hospitalization rates among unvaccinated persons without a previous COVID-19 diagnosis, hospitalization rates in California followed a similar pattern. These relationships changed after the SARS-CoV-2 Delta variant became predominant (i.e., accounted for >50% of sequenced isolates) in late June and July. By the week beginning October 3, compared with COVID-19 cases rates among unvaccinated persons without a previous COVID-19 diagnosis, case rates among vaccinated persons without a previous COVID-19 diagnosis were 6.2-fold (California) and 4.5-fold (New York) lower; rates were substantially lower among both groups with previous COVID-19 diagnoses, including 29.0-fold (California) and 14.7-fold lower (New York) among unvaccinated persons with a previous diagnosis, and 32.5-fold (California) and 19.8-fold lower (New York) among vaccinated persons with a previous diagnosis of COVID-19. During the same period, compared with hospitalization rates among unvaccinated persons without a previous COVID-19 diagnosis, hospitalization rates in California followed a similar pattern. These results demonstrate that vaccination protects against COVID-19 and related hospitalization, and that surviving a previous infection protects against a reinfection and related hospitalization. Importantly, infection-derived protection was higher after the Delta variant became predominant, a time when vaccine-induced immunity for many persons declined because of immune evasion and immunologic waning (2,5,6). Similar cohort data accounting for booster doses needs to be assessed, as new variants, including Omicron, circulate. Although the epidemiology of COVID-19 might change with the emergence of new variants, vaccination remains the safest strategy to prevent SARS-CoV-2 infections and associated complications; all eligible persons should be up to date with COVID-19 vaccination. Additional recommendations for vaccine doses might be warranted in the future as the virus and immunity levels change.

Four cohorts of persons aged ≥18 years were assembled via linkages of records from electronic laboratory reporting databases and state-specific immunization information systems. Persons were classified based on whether they had had a laboratory-confirmed SARS-CoV-2 infection by March 1, 2021 (i.e., previous COVID-19 diagnosis)§; had received at least the primary COVID-19 vaccination series by May 16, 2021; had a previous COVID-19 diagnosis and were fully vaccinated**; or had neither received a previous COVID-19 diagnosis by March 1 nor received a first COVID-19 vaccine dose by the end of the analysis period. The size of the unvaccinated group without a previous diagnosis was derived by subtracting the observed groups from U.S. Census estimates.†† To maintain each defined cohort, persons who received a COVID-19 diagnosis during March 1–May 30, 2021, or who died before May 30, 2021, were excluded (to maintain eligibility for incident cases for all cohorts on May 30, 2021),§§ as were persons who received a first vaccine dose during May 30–November 20, 2021. During May 30–November 20, 2021, incident cases were defined using a positive nucleic acid amplification test (NAAT) result from the California COVID-19 Reporting System (CCRS) or a positive NAAT or antigen test result from the New York Electronic Clinical Laboratory Reporting System. In California, person-level hospitalization data from CCRS and supplementary hospitalization reports were used to identify COVID-19–associated hospitalizations. A lifetable method was used to calculate hazard rates (average daily cases during a 7-day interval or hospitalizations over a 14-day interval), hazard ratios, and 95% CIs for each cohort. Rates were age-adjusted to 2000 U.S. Census data using direct standardization.¶¶ Supplementary analyses stratified case rates by timing of previous diagnoses and primary series vaccine product. SAS (version 9.4; SAS Institute) and R (version 4.0.4; The R Foundation) were used to conduct all analyses. Institutional review boards (IRBs) in both states determined this surveillance activity to be necessary for public health work, and therefore, it did not require IRB review.

Approximately three quarters of adults from California (71.2%) and New York (72.2%) included in this analysis were vaccinated and did not have a previous COVID-19 diagnosis; however, 18.0% of California residents and 18.4% of New York residents were unvaccinated with no previous COVID-19 diagnosis (Table 1). In both states, 4.5% of persons were vaccinated and had a previous COVID-19 diagnosis; 6.3% in California and 4.9% in New York were unvaccinated with a previous diagnosis. Among 1,108,600 incident COVID-19 cases in these cohorts (752,781 in California and 355,819 in New York), the median intervals from vaccination or previous COVID-19 diagnosis to incident diagnosis were slightly shorter in California (138–150 days) than in New York (162–171 days).

Before the Delta variant became predominant in each state’s U.S. Department of Health and Human Services region (June 26 in Region 9 [California] and July 3 in Region 2 [New York]),*** the highest incidence was among unvaccinated persons without a previous COVID-19 diagnosis; during this time, case rates were relatively low among the three groups with either previous infection or vaccination and were lowest among vaccinated persons without a previous COVID-19 diagnosis (Supplementary Figure 1, https://stacks.cdc.gov/view/cdc/113253) (Supplementary Figure 2, https://stacks.cdc.gov/view/cdc/113253). During the week beginning May 30, 2021, compared with COVID-19 case rates among unvaccinated persons without a previous COVID-19 diagnosis, COVID-19 case rates were 19.9-fold (California) and 18.4-fold (New York) lower among vaccinated persons without a previous diagnosis; rates were 7.2-fold (California) and 9.9-fold (New York) lower among unvaccinated persons with a previous COVID-19 diagnosis and 9.6-fold (California) and 8.5-fold (New York) lower among vaccinated persons with a previous COVID-19 diagnosis (Table 2).

As the Delta variant prevalence increased to >95% (97% in Region 9 and 98% in Region 2 on August 1), rates increased more rapidly among the vaccinated group with no previous COVID-19 diagnosis than among both the vaccinated and unvaccinated groups with a previous COVID-19 diagnosis (Supplementary Figure 1, https://stacks.cdc.gov/view/cdc/113253) (Supplementary Figure 2, https://stacks.cdc.gov/view/cdc/113253). For example, during the week of October 3, compared with rates among unvaccinated persons without a previous COVID-19 diagnosis, rates among vaccinated persons without a previous diagnosis were 6.2-fold lower (95% CI = 6.0–6.4) in California and 4.5-fold lower (95% CI = 4.3–4.7) in New York (Table 2). Further, rates among unvaccinated persons with a previous COVID-19 diagnosis were 29-fold lower (95% CI = 25.0–33.1) than rates among unvaccinated persons without a previous COVID-19 diagnosis in California and 14.7-fold lower (95% CI = 12.6–16.9) in New York. Rates among vaccinated persons who had had COVID-19 were 32.5-fold lower (95% CI = 27.5–37.6) than rates among unvaccinated persons without a previous COVID-19 diagnosis in California and 19.8-fold lower (95% CI = 16.2–23.5) in New York. Rates among vaccinated persons without a previous COVID-19 diagnosis were consistently higher than rates among unvaccinated persons with a history of COVID-19 (3.1-fold higher [95% CI = 2.6–3.7] in California and 1.9-fold higher [95% CI = 1.5–2.3] in New York) and rates among vaccinated persons with a history of COVID-19 (3.6-fold higher [95% CI = 2.9–4.3] in California and 2.8-fold higher [95% CI = 2.1–3.4] in New York).

COVID-19 hospitalization rates in California were always highest among unvaccinated persons without a previous COVID-19 diagnosis (Table 2) (Figure). In the pre-Delta period during June 13–June 26, for example, compared with hospitalization rates among unvaccinated persons without a previous COVID-19 diagnosis, hospitalization rates were 27.7-fold lower (95% CI = 22.4–33.0) among vaccinated persons without a previous COVID-19 diagnosis, 6.0-fold lower (95% CI = 3.3–8.7) among unvaccinated persons with a previous COVID-19 diagnosis, and 7.1-fold lower (95% CI = 4.0–10.3) among vaccinated persons with a previous COVID-19 diagnosis. However, this pattern also shifted as the Delta variant became predominant. During October 3–16, compared with hospitalization rates among unvaccinated persons without a previous COVID-19 diagnosis, hospitalization rates were 19.8-fold lower (95% CI = 18.2–21.4) among vaccinated persons without a previous COVID-19 diagnosis, 55.3-fold lower (95% CI = 27.3–83.3) among unvaccinated persons with a previous COVID-19 diagnosis, and 57.5-fold lower (95% CI = 29.2–85.8) among vaccinated persons with a previous COVID-19 diagnosis.

Among the two cohorts with a previous COVID-19 diagnosis, no consistent incidence gradient by time since the previous diagnosis was observed (Supplementary Figure 3, https://stacks.cdc.gov/view/cdc/113253). When the vaccinated cohorts were stratified by the vaccine product received, among vaccinated persons without a previous COVID-19 diagnosis, the highest incidences were observed among persons receiving the Janssen (Johnson & Johnson), followed by Pfizer-BioNTech, then Moderna vaccines (Supplementary Figure 4, https://stacks.cdc.gov/view/cdc/113253). No pattern by product was observed among vaccinated persons with a previous COVID-19 diagnosis.

Discussion

This analysis integrated laboratory testing, hospitalization surveillance, and immunization registry data in two large states during May–November 2021, before widespread circulation of the SARS-CoV-2 Omicron variant and before most persons had received additional or booster COVID-19 vaccine doses to protect against waning immunity. Rate estimates from the analysis describe different experiences stratified by COVID-19 vaccination status and previous COVID-19 diagnosis and during times when different SARS-CoV-2 variants predominated. Case rates were initially lowest among vaccinated persons without a previous COVID-19 diagnosis; however, after emergence of the Delta variant and over the course of time, incidence increased sharply in this group, but only slightly among both vaccinated and unvaccinated persons with previously diagnosed COVID-19 (6). Across the entire study period, persons with vaccine- and infection-derived immunity had much lower rates of hospitalization compared with those in unvaccinated persons. These results suggest that vaccination protects against COVID-19 and related hospitalization and that surviving a previous infection protects against a reinfection. Importantly, infection-derived protection was greater after the highly transmissible Delta variant became predominant, coinciding with early declining of vaccine-induced immunity in many persons (5). Similar data accounting for booster doses and as new variants, including Omicron, circulate will need to be assessed.

The understanding and epidemiology of COVID-19 has shifted substantially over time with the emergence and circulation of new SARS-CoV-2 variants, introduction of vaccines, and changing immunity as a result. Similar to the early period of this study, two previous U.S. studies found more protection from vaccination than from previous infection during periods before Delta predominance (3,7). As was observed in the present study after July, recent international studies have also demonstrated increased protection in persons with previous infection, with or without vaccination, relative to vaccination alone†††, §§§ (4). This might be due to differential stimulation of the immune response by either exposure type.¶¶¶ Whereas French and Israeli population-based studies noted waning protection from previous infection, this was not apparent in the results from this or other large U.K. and U.S. studies**** (4,8). Further studies are needed to establish duration of protection from previous infection by variant type, severity, and symptomatology, including for the Omicron variant.

The findings in this report are subject to at least seven limitations. First, analyses were not stratified by time since vaccine receipt, but only by time since previous diagnosis, although earlier studies have examined waning of vaccine-induced immunity (Supplementary Figure 3, https://stacks.cdc.gov/view/cdc/113253) (2). Second, persons with undiagnosed infection are misclassified as having no previous COVID-19 diagnosis; however, this misclassification likely results in a conservative bias (i.e., the magnitude of difference in rates would be even larger if misclassified persons were not included among unvaccinated persons without a previous COVID-19 diagnosis). California seroprevalence data during this period indicate that the ratio of actual (presumptive) infections to diagnosed cases among adults was 2.6 (95% CI = 2.2–2.9).†††† Further, California only included NAAT results, whereas New York included both NAAT and antigen test results. However, antigen testing made up a smaller percentage of overall testing volume reported in California (7% of cases) compared with New York (25% of cases) during the study period. Neither state included self-tests, which are not easily reportable to public health. State-specific hazard ratios were generally comparable, although differences in rates among unvaccinated persons with a previous COVID-19 diagnosis were noteworthy. Third, potential exists for bias related to unmeasured confounding (e.g., behavioral or geographic differences in exposure risk) and uncertainty in the population size of the unvaccinated group without a previous COVID-19 diagnosis. Persons might be more or less likely to receive testing based on previous diagnosis or vaccination status; however, different trajectories between vaccinated persons with and without a previous COVID-19 diagnosis, and similar findings for cases and hospitalizations, suggest that these biases were minimal. Fourth, this analysis did not include information on the severity of initial infection and does not account for the full range of morbidity and mortality represented by the groups with previous infections. Fifth, this analysis did not ascertain receipt of additional or booster COVID-19 vaccine doses and was conducted before many persons were eligible or had received additional or booster vaccine doses, which have been shown to confer additional protection.§§§§ Sixth, some estimates lacked precision because of sample size limitations. Finally, this analysis was conducted before the emergence of the Omicron variant, for which vaccine or infection-derived immunity might be diminished.¶¶¶¶ This study offers a surveillance data framework to help evaluate both infections in vaccinated persons and reinfections as new variants continue to emerge.

Vaccination protected against COVID-19 and related hospitalization, and surviving a previous infection protected against a reinfection and related hospitalization during periods of predominantly Alpha and Delta variant transmission, before the emergence of Omicron; evidence suggests decreased protection from both vaccine- and infection-induced immunity against Omicron infections, although additional protection with widespread receipt of booster COVID-19 vaccine doses is expected. Initial infection among unvaccinated persons increases risk for serious illness, hospitalization, long-term sequelae, and death; by November 30, 2021, approximately 130,781 residents of California and New York had died from COVID-19. Thus, vaccination remains the safest and primary strategy to prevent SARS-CoV-2 infections, associated complications, and onward transmission. Primary COVID-19 vaccination, additional doses, and booster doses are recommended by CDC’s Advisory Committee on Immunization Practices to ensure that all eligible persons are up to date with COVID-19 vaccination, which provides the most robust protection against initial infection, severe illness, hospitalization, long-term sequelae, and death.***** Additional recommendations for vaccine doses might be warranted in the future as the virus and immunity levels change.

Acknowledgments

Dana Jaffe, California Department of Public Health; Rebecca Hoen, Meng Wu, New York State Department of Health; Citywide Immunization Registry Program, New York City Department of Health and Mental Hygiene.

Corresponding author: Tomás M. León, tomas.leon@cdph.ca.gov.


1California Department of Public Health; 2New York State Department of Health; 3University at Albany School of Public Health, SUNY, Rensselaer, New York; 4CDC.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

 https://covid.cdc.gov/covid-data-tracker/#cases_deathsper100klast7days

 Statewide immunization databases in California are the California Immunization Registry, Regional Immunization Data Exchange, and San Diego Immunization Registry; the laboratory system is the California COVID Reporting System (CCRS). In New York, immunization information systems include Citywide Immunization Registry and the New York State Immunization Information System; the laboratory system is the Electronic Clinical Laboratory Reporting System (ECLRS). California data were matched between the immunization and case registries using a probabilistic algorithm with exact match for zip code and date of birth and fuzzy match on first name and last name. New York data were matched to the ECLRS with the use of a deterministic algorithm based on first name, last name, and date of birth. In California, person-level hospitalization data from CCRS and supplementary hospitalization reports were used to identify COVID-19–associated hospitalizations.

§ For both classification into cohorts of persons with previous COVID-19 diagnoses and for measuring incident cases, laboratory-confirmed infection was defined as the receipt of a new positive SARS-CoV-2 nucleic acid amplification test (NAAT) or antigen test (both for New York and NAAT only for California) result, but not within 90 days of a previous positive result.

 Fully vaccinated with the primary vaccination series is defined as receipt of a second dose of an mRNA COVID-19 vaccine (Pfizer-BioNTech or Moderna) or 1 dose of the Janssen (Johnson & Johnson) vaccine ≥14 days before May 30, 2021.

** Because of the timing of full vaccination, the cohort definitions, and analysis timeframe, this cohort consisted nearly exclusively of persons who had previously received a laboratory-confirmed diagnosis of COVID-19 and later were fully vaccinated (California: 99.9%, New York: 99.7%), as opposed to the reverse order.

†† Whereas vaccinated cohorts were directly observed in the immunization information system databases, unvaccinated persons without a previous COVID-19 diagnosis were defined using U.S. Census population estimates minus the number of persons partially or fully vaccinated by December 11, 2021, and unvaccinated persons with a previous laboratory-confirmed infection before May 30, 2021. In California, the California Department of Finance population estimates were used for 2020, and the 2018 CDC National Center for Health Statistics Bridged Race file for U.S. Census population estimates were used in New York, consistent with other COVID-19 surveillance reporting.

§§ In California, a person-level match was performed to exclude deaths in each cohort before May 30, 2021. In New York, COVID-19 deaths were removed in aggregate from the starting number of unvaccinated persons with a previous COVID-19 diagnosis on May 30, 2021.

¶¶ https://www.cdc.gov/nchs/data/statnt/statnt20.pdfpdf icon

*** https://covid.cdc.gov/covid-data-tracker/#variant-proportions

††† https://www.medrxiv.org/content/10.1101/2021.09.12.21263461v1external icon

§§§ https://www.medrxiv.org/content/10.1101/2021.11.29.21267006v1external icon

¶¶¶ https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/vaccine-induced-immunity.html#anchor_1635540449320

**** https://www.medrxiv.org/content/10.1101/2021.12.04.21267114v1external icon

†††† https://www.medrxiv.org/content/10.1101/2021.12.09.21267565v1external icon

§§§§ https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status

¶¶¶¶ https://www.medrxiv.org/content/10.1101/2021.12.30.21268565v1external iconhttps://www.medrxiv.org/content/10.1101/2022.01.07.22268919v1external icon

***** https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html

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