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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References

  1. Rosenberg ES, Holtgrave DR, Dorabawila V, et al. New COVID-19 cases and hospitalizations among adults, by vaccination status—New York, May 3–July 25, 2021. MMWR Morb Mortal Wkly Rep 2021;70:1306–11. https://doi.org/10.15585/mmwr.mm7037a7external icon PMID:34529645external icon
  2. Rosenberg ES, Dorabawila V, Easton D, et al. Covid-19 vaccine effectiveness in New York State. N Engl J Med 2021. Epub December 1, 2021. https://doi.org/10.1056/NEJMoa2116063external icon PMID:34942067external icon
  3. Cavanaugh AM, Spicer KB, Thoroughman D, Glick C, Winter K. Reduced risk of reinfection with SARS-CoV-2 after COVID-19 vaccination—Kentucky, May–June 2021. MMWR Morb Mortal Wkly Rep 2021;70:1081–3. https://doi.org/10.15585/mmwr.mm7032e1external icon PMID:34383732external icon
  4. Grant R, Charmet T, Schaeffer L, et al. Impact of SARS-CoV-2 Delta variant on incubation, transmission settings and vaccine effectiveness: Results from a nationwide case-control study in France. Lancet Reg Health Eur 2021. Epub November 26, 2021.  https://doi.org/10.1016/j.lanepe.2021.100278external icon
  5. Self WH, Tenforde MW, Rhoads JP, et al.; IVY Network. Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions—United States. MMWR Morb Mortal Wkly Rep 2021;70:1337–43. https://doi.org/10.15585/mmwr.mm7038e1external icon PMID:34555004external icon
  6. Lin D-Y, Gu Y, Wheeler B, et al. Effectiveness of Covid-19 vaccines in the United States over 9 months: surveillance data from the state of North Carolina. [Preprint posted online October 26, 2021.] https://www.medrxiv.org/content/10.1101/2021.10.25.21265304v1external icon
  7. Bozio CH, Grannis SJ, Naleway AL, et al. Laboratory-confirmed COVID-19 among adults hospitalized with COVID-19–like illness with infection-induced or mRNA vaccine-induced SARS-CoV-2 immunity—nine states, January–September 2021. MMWR Morb Mortal Wkly Rep 2021;70:1539–44. https://doi.org/10.15585/mmwr.mm7044e1external icon PMID:34735425external icon
  8. Kim P, Gordon SM, Sheehan MM, Rothberg MB. Duration of SARS-CoV-2 natural immunity and protection against the Delta variant: a retrospective cohort study. Clin Infect Dis 2021. Epub December 3, 2021. https://doi.org/10.1093/cid/ciab999external icon PMID:34864907external icon

Necessity of COVID-19 Vaccination in Persons Who Have Already Had COVID-19

Authors: Nabin K ShresthaPatrick C BurkeAmy S NowackiPaul TerpelukSteven M Gordon

Clinical Infectious Diseases, ciac022, https://doi.org/10.1093/cid/ciac022

The purpose of this study was to evaluate the necessity of COVID-19 vaccination in persons with prior COVID-19.Methods

Employees of Cleveland Clinic working in Ohio on Dec 16, 2020, the day COVID-19 vaccination was started, were included. Anyone who tested positive for COVID-19 at least once before the study start date was considered previously infected. One was considered vaccinated 14 days after receiving the second dose of a COVID-19 mRNA vaccine. The cumulative incidence of COVID-19, symptomatic COVID-19, and hospitalizations for COVID-19, were examined over the next year.Results

Among 52238 employees, 4718 (9%) were previously infected, and 36922 (71%) were vaccinated by the study’s end. Cumulative incidence of COVID-19 was substantially higher throughout for those previously uninfected who remained unvaccinated than for all other groups, lower for the vaccinated than unvaccinated, and lower for those previously infected than those not. Incidence of COVID-19 increased dramatically in all groups after the Omicron variant emerged. In multivariable Cox proportional hazards regression, both prior COVID-19 and vaccination were independently associated with significantly lower risk of COVID-19. Among previously infected subjects, a lower risk of COVID-19 overall was not demonstrated, but vaccination was associated with a significantly lower risk of symptomatic COVID-19 in both the pre-Omicron (HR 0.60, 95% CI 0.40–0.90) and Omicron (HR 0.36, 95% CI 0.23–0.57) phases.Conclusions

Both previous infection and vaccination provide substantial protection against COVID-19. Vaccination of previously infected individuals does not provide additional protection against COVID-19 for several months, but after that provides significant protection at least against symptomatic COVID-19.SARS-CoV-2COVID-19IncidenceVaccinesImmunityTopic: 

Issue Section: Major Article PDF

New York Times Admits Unvaxxed People Have ‘Lower Rates of Infection And Hospitalization’ Of COVID-19 Than The Vaxxed.

Authors: Natalie Winters

A January 19th update posted to the outlet’s COVID-19 live blog explains how unvaccinated individuals who previously contracted the virus “had lower rates of infection and hospitalization than those protected by vaccines alone”:

During the week beginning May 30, 2021, vaccinated people who had not experienced Covid had the lowest risk of coronavirus infection and hospitalization, followed by unvaccinated people who had been previously diagnosed with Covid.

By the week beginning Oct. 3, however, vaccinated people with a prior diagnosis fared best against the Delta variant. Unvaccinated people with a history of Covid also had lower rates of infection and hospitalization than those protected by vaccines alone.

“The data are consistent with trends observed in international studies, the researchers said,” added The New York Times.

The outlet attempts to explain the disparity in vaccinated and unvaccinated people contracting COVID-19 by attributing it to the “waning of vaccine-derived immunity.”

“A recent study of employees at the Cleveland Clinic suggested that while vaccination does not add much benefit to a prior bout for the first many months, it may offer better protection against symptomatic illness over the long term than does immunity from a previous infection,” reasons the outlet.

The admission follows other studies showing similar trends, including a Robert Koch Institute report that found nearly 80 percent of Omicron cases occurred in vaccinated individuals. The story also follows an unprecedented surge in lobbying efforts by American pharmaceutical giants that developed COVID-19 shots including Pfizer and Moderna.

Representing yet another conflict of interest, a member of Pfizer’s Board of Directors doubles as a Chairman for Reuters, which has published more than 22,000 articles mentioning the Chinese Communist Party-linked pharmaceutical giant.

New data show those who recovered from Covid-19 were less likely than vaccinated to get infected during Delta wave

New data released Wednesday showed that both vaccination and prior infection offered strong protection against infection and hospitalization from Covid-19 during the Delta wave — and that case and hospitalization rates were actually lower among people who had recovered from Covid-19 than among those who had been vaccinated.

The data, released by the Centers for Disease Control and Prevention and health agencies in California and New York, are sure to inflame arguments from those who insist they don’t need to be vaccinated if they can show they’ve recovered from Covid-19. But the data contain many caveats that health officials stressed pointed to the value of vaccination, even on top of prior infection.

For one, the new report was based on data only through November, before the U.S. booster campaign really took off. It also looked at data during the Delta wave and does not account for the surging Omicron variant.

And while research has shown that infection can train the immune system to guard against the coronavirus in different ways than vaccination, Covid-19 also has killed more than 850,000 people in this country, sickened — often severely — millions more, and caused untold cases of long Covid. Serious side effects from the Covid-19 vaccines are extremely rare.

“We know that vaccination remains the safest strategy for protecting against Covid-19,” Benjamin Silk, a CDC epidemiologist, told reporters Wednesday.

The data also confirmed something we’ve known for a long time: Those who weren’t vaccinated and also hadn’t been previously infected were far more likely to be infected and hospitalized than either group.

The new report examined Covid-19 trends among adults in New York and California from May 30 to Nov. 20, 2021.

In early October, after Delta became dominant, infection rates among vaccinated people who hadn’t had Covid were 6.2-fold lower than among unvaccinated people who hadn’t had Covid-19 in California, and 4.5-fold lower in New York. People who previously had Covid-19 but had not been vaccinated had 29-fold (California) and 14.7-fold (New York) lower case rates. Vaccinated people who had also had Covid-19 had the lowest rates, with a 32.5-fold (California) and 19.8-fold (New York) lower infection rate than people who had no protection.

Hospitalization rates in California followed a similar pattern, the report says. (There were no hospitalization data from New York.) In October, hospitalization rates for people who’d been vaccinated but hadn’t had Covid were 19.8-fold lower than among those who hadn’t had Covid-19 or been vaccinated. The rates were 55.3-fold lower among unvaccinated people who’d had Covid-19, and 57.5-fold lower among people who’d been vaccinated and had Covid-19.

Erica Pan, California’s state epidemiologist, said hospitalizations among those who were vaccinated were mostly among older people.

Incidences among people who’d been vaccinated were highest among people who received the Johnson & Johnson shot, followed by the Pfizer-BioNTech and then the Moderna shots, the report said.

“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,” the report states. Immune evasion refers to how, as the virus evolved, it started to erode the protection elicited by vaccination or an infection from an earlier form of the virus; this happened to some degree with the Delta variant, and to a much larger extent with the Omicron variant.

The new CDC report notes that the analyzed data are from the period before most people had received additional shots. It was only in mid-October, for example, that the government authorized booster shots for people who had received the J&J vaccine, recommending that people get them two months after the original jab of the one-dose shot. Boosters weren’t given the green light for all adults until November.

T-Cells “Minimize” Damage Caused By Omicron, Studies Show

Authors: Joseph Adinolfi Jr. 

Two new studies – one from Erasmus University in the Netherlands and one from the University of Cape Town in South Africa – have just reminded humanity that our antibodies aren’t the last line of defense against COVID, and its newest variant, omicron.

Both have confirmed that T-cells, what Bloomberg describes as the body’s weapon against every virus-infected cell, have shown a surprising ability to defend against omicron.

The report goes on to explain that T-cells are the reason why mortality hasn’t increased alongside the advent of omicron: with or without vaccines, the human body still has a tool in its toolkit to suppress viruses like these. The T-cell’s most critical attribute, when it comes to fighting viruses, is that they target the whole of the spike protein that viruses use to bind with human cells. Because of this, mutations that impact the spike protein (omicron was said to have 50 pertinent mutations in that department) won’t help it evade the T-cell response.

For their study, the Dutch researchers looked at 60 vaccinated health-care workers and found that while their antibody responses to omicron were lower or nonexistent (compared with the beta or delta), their T cell responses were largely unaltered and still potent, “potentially balancing the lack of neutralizing antibodies in preventing or limiting severe Covid-19,” according to the study.

The other study, from the University of Cape Town’s Institute of Infectious Disease and Molecular Medicine, looked at recovered COVID patients, and those who had been vaccinated with the Pfizer or J&J jabs.

While antibodies didn’t fare well, they found that 70% to 80% of the T-cell responses were able to suppress omicron.

Vaccines are helpful in that they help induce a T-cell response to the virus, according to the Dutch researchers. Overall, these results demonstrate that vaccination and infection induce a robust CD4 and CD8 T-cell response that largely cross-reacts with omicron, consistent with recent work from our laboratory and others on limited T-cell escape by Beta, Delta and other variants…”

The Dutch summarized the data from their study in a pair of figures, presented below:

New Israeli Study Finds Fully Vaccinated People are at “Greater Risk of Hospitalization” and 13 TIMES MORE LIKELY to Catch Covid-19 Than Those Who Have Recovered and Have Natural Immunity

Authors: By Julian Conradson Published August 27, 2021 at 2:06pm

A new study out of Israel has seemingly confirmed that individuals who have natural immunity have better protection against the NEW DELTA VARIANT than people who are fully vaccinated.

The team of researchers, from Maccabi Healthcare and Tel Aviv University, published their study earlier this week to medRxiv.org.

‘This study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, ‘ the team of researchers wrote

Not just a little bit better either. People who have taken both doses of the Pfizer jab are 13 TIMES more likely to have a breakthrough infection, and are even at a “greater risk for Covid-19 hospitalizations.”

The researchers conducted an extensive study on 800,000 individuals that were broken into 3 groups. People who had received either one or two doses of the Pfizer-BioNTech COVID-19 vaccine were compared with unvaccinated individuals who have natural immunity, because they had already recovered from the virus.

SARS-CoV-2-naïve vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. 

When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naïve vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naïve vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected.

MOST NOTABLY, the study also found – Three months after a 2nd dose, the risk of contracting Covid was 13.06 times higher among the vaccinated and they are 27 TIMES more likely to experience symptoms.

After adjusting for comorbidities, we found a 27.02-fold risk (95% CI, 12.7 to 57.5) for symptomatic breakthrough infection as opposed to symptomatic reinfection (P<0.001) (Table 2b). None of the covariates were significant, except for age ≥60 years. 

So, to get this straight – According to these highly credible researchers who conducted a massive study on hundreds of thousands of people, the Pfizer-BioNTech vaccine won’t just make people more likely to catch new variants – they will also be more affected by symptoms and more likely to end up hospitalized.

This latest data just adds to a mounting pile of evidence that demonstrates the experimental jab’s low efficacy when it comes to stopping the spread of the virus. Even before this most recent study, some researchers had already found that the vaccinated spread the virus as much, if not more, than the unvaxxed.

The FDA skipped out on necessary trials and rubber-stamped their experimental jab anyway.

According to available data, a third of the entire US population had contracted Covid BY THE END OF 2020.

Natural immunity is not new.. It has consistently proven to be superior to inoculation. If 1/3rd of Americans had already contracted the virus – before it had even been known for a full year – then why would “everyone” need to take their experimental vaccine?

Well…

The authoritarian health regime in the US, led by Furor Dr. Fauci, has been flip-flopping since their comrades in thee CCP unleashed the virus on the world.

They are wholly unconcerned with saving anyone and are fully invested in using lockdowns and freedom-crushing restrictions to tighten their grip on power. 

Mindless compliance hasn’t worked so now they must start forcing people in other ways.