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.
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.
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 1, 2). 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 3, 4). 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).
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).
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).
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.
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 1, 4). 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.
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.
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).
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.
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.
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.
Relevant data are available from the corresponding author upon reasonable request.
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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.
Vaccines currently are the primary mitigation strategy to combat COVID-19 around the world. For instance, the narrative related to the ongoing surge of new cases in the United States (US) is argued to be driven by areas with low vaccination rates . A similar narrative also has been observed in countries, such as Germany and the United Kingdom . At the same time, Israel that was hailed for its swift and high rates of vaccination has also seen a substantial resurgence in COVID-19 cases . We investigate the relationship between the percentage of population fully vaccinated and new COVID-19 cases across 68 countries and across 2947 counties in the US.
We used COVID-19 data provided by the Our World in Data for cross-country analysis, available as of September 3, 2021 (Supplementary Table 1) . We included 68 countries that met the following criteria: had second dose vaccine data available; had COVID-19 case data available; had population data available; and the last update of data was within 3 days prior to or on September 3, 2021. For the 7 days preceding September 3, 2021 we computed the COVID-19 cases per 1 million people for each country as well as the percentage of population that is fully vaccinated.
For the county-level analysis in the US, we utilized the White House COVID-19 Team data , available as of September 2, 2021 (Supplementary Table 2). We excluded counties that did not report fully vaccinated population percentage data yielding 2947 counties for the analysis. We computed the number and percentages of counties that experienced an increase in COVID-19 cases by levels of the percentage of people fully vaccinated in each county. The percentage increase in COVID-19 cases was calculated based on the difference in cases from the last 7 days and the 7 days preceding them. For example, Los Angeles county in California had 18,171 cases in the last 7 days (August 26 to September 1) and 31,616 cases in the previous 7 days (August 19–25), so this county did not experience an increase of cases in our dataset. We provide a dashboard of the metrics used in this analysis that is updated automatically as new data is made available by the White House COVID-19 Team (https://tiny.cc/USDashboard).
At the country-level, there appears to be no discernable relationship between percentage of population fully vaccinated and new COVID-19 cases in the last 7 days (Fig. 1). In fact, the trend line suggests a marginally positive association such that countries with higher percentage of population fully vaccinated have higher COVID-19 cases per 1 million people. Notably, Israel with over 60% of their population fully vaccinated had the highest COVID-19 cases per 1 million people in the last 7 days. The lack of a meaningful association between percentage population fully vaccinated and new COVID-19 cases is further exemplified, for instance, by comparison of Iceland and Portugal. Both countries have over 75% of their population fully vaccinated and have more COVID-19 cases per 1 million people than countries such as Vietnam and South Africa that have around 10% of their population fully vaccinated.
Across the US counties too, the median new COVID-19 cases per 100,000 people in the last 7 days is largely similar across the categories of percent population fully vaccinated (Fig. 2). Notably there is also substantial county variation in new COVID-19 cases within categories of percentage population fully vaccinated. There also appears to be no significant signaling of COVID-19 cases decreasing with higher percentages of population fully vaccinated (Fig. 3).
Median, interquartile range and variation in cases per 100,000 people in the last 7 days across percentage of population fully vaccinated as of September 2, 2021Full size image
Of the top 5 counties that have the highest percentage of population fully vaccinated (99.9–84.3%), the US Centers for Disease Control and Prevention (CDC) identifies 4 of them as “High” Transmission counties. Chattahoochee (Georgia), McKinley (New Mexico), and Arecibo (Puerto Rico) counties have above 90% of their population fully vaccinated with all three being classified as “High” transmission. Conversely, of the 57 counties that have been classified as “low” transmission counties by the CDC, 26.3% (15) have percentage of population fully vaccinated below 20%.
Since full immunity from the vaccine is believed to take about 2 weeks after the second dose, we conducted sensitivity analyses by using a 1-month lag on the percentage population fully vaccinated for countries and US counties. The above findings of no discernable association between COVID-19 cases and levels of fully vaccinated was also observed when we considered a 1-month lag on the levels of fully vaccinated (Supplementary Figure 1, Supplementary Figure 2).
We should note that the COVID-19 case data is of confirmed cases, which is a function of both supply (e.g., variation in testing capacities or reporting practices) and demand-side (e.g., variation in people’s decision on when to get tested) factors.
The sole reliance on vaccination as a primary strategy to mitigate COVID-19 and its adverse consequences needs to be re-examined, especially considering the Delta (B.1.617.2) variant and the likelihood of future variants. Other pharmacological and non-pharmacological interventions may need to be put in place alongside increasing vaccination rates. Such course correction, especially with regards to the policy narrative, becomes paramount with emerging scientific evidence on real world effectiveness of the vaccines.
For instance, in a report released from the Ministry of Health in Israel, the effectiveness of 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine against preventing COVID-19 infection was reported to be 39% , substantially lower than the trial efficacy of 96% . It is also emerging that immunity derived from the Pfizer-BioNTech vaccine may not be as strong as immunity acquired through recovery from the COVID-19 virus . A substantial decline in immunity from mRNA vaccines 6-months post immunization has also been reported . Even though vaccinations offers protection to individuals against severe hospitalization and death, the CDC reported an increase from 0.01 to 9% and 0 to 15.1% (between January to May 2021) in the rates of hospitalizations and deaths, respectively, amongst the fully vaccinated .
In summary, even as efforts should be made to encourage populations to get vaccinated it should be done so with humility and respect. Stigmatizing populations can do more harm than good. Importantly, other non-pharmacological prevention efforts (e.g., the importance of basic public health hygiene with regards to maintaining safe distance or handwashing, promoting better frequent and cheaper forms of testing) needs to be renewed in order to strike the balance of learning to live with COVID-19 in the same manner we continue to live a 100 years later with various seasonal alterations of the 1918 Influenza virus.
Authors: DYLAN HOUSMAN HEALTHCARE REPORTER August 28, 20215:12 PM ET
A new study of the power of COVID-19 natural immunity versus the protection provided by vaccines is igniting further debate among scientists on how to assess risk from the virus.
The observational study of more than 700,000 Israelis, which hasn’t yet been peer-reviewed, compared three groups: those who hadn’t been infected and received two doses of Pfizer’s COVID-19 vaccine, those who had been infected and were completely unvaccinated and individuals who were previously infected and received one dose of the vaccine. The researchers found that uninfected vaccine recipients were 13 times more likely to experience a breakthrough infection than those who were previously infected.
“It’s a textbook example of how natural immunity is really better than vaccination,” Charlotte Thålin, a physician and immunology researcher at Danderyd Hospital and the Karolinska Institute in Stockholm, Sweden, told Science Magazine. “To my knowledge, it’s the first time [this] has really been shown in the context of COVID-19.”
Prior research has indicated that natural immunity to COVID-19 is strong, but no research has definitely shown that it is more protective than getting vaccinated up to this point.
The increased protection found in the study extended beyond reinfection, as natural immunity was also found to lead to fewer symptomatic cases and hospitalizations as well. The researchers also concluded that individuals who received one dose of the Pfizer vaccine in addition to recovering from previous infection had the highest level of protection of the three groups.
“The differences are huge,” added Thålin, although she warned the research couldn’t be considered conclusive. The sample size of hospitalizations in the 32,000-person analysis of the vaccinated group was only eight, and only one among the previously infected. Nobody in the entire study died, signaling that both vaccination and natural immunity provide a substantial amount of protection from death.
Researchers warned that the takeaway from the study should not be that catching COVID-19 is a superior substitute to getting vaccinated, due to the higher level of risk that comes with battling the virus versus getting the shot. “What we don’t want people to say is: ‘All right, I should go out and get infected, I should have an infection party,” Rockefeller University’s Michael Nussenzweig, an immunologist, told Science.
As many countries are going through another wave of infections, including some where the vast majority of the population has been vaccinated, many are starting to despair that we’ll never see the end of the pandemic. In this post, I will argue that, on the contrary, not only is the pandemic already on its way out, but the virus will be relatively harmless after it has become endemic. This is going to happen not because the SARS-CoV-2 will become intrinsically less dangerous, although it might, but rather because what made the virus so dangerous was that nobody had immunity against it, so once it has become endemic it will infect fewer people and even those who end up infected will be much less at risk. Moreover, I will explain that, despite widespread anxiety about the emergence of new variants and the danger of immune evasion, the fact that SARS-CoV-2 is mutating will not prevent this outcome because of the way immunity works. Finally, I will argue that, although some people are calling to pursue the eradication of SARS-CoV-2 (as we have done with smallpox), we almost certainly couldn’t eradicate it even if we wanted to and that even if we could it wouldn’t be worth it.
SARS-CoV-2 is going to become mostly harmless
You may have heard that, as they evolve, viruses necessarily become less lethal because it makes no evolutionary sense for them to kill the hosts on which they depend for their survival and reproduction, but this is a myth and it’s not what I’m saying. The claim I’m making is based on a much sounder and more straightforward argument. But to understand why it’s true, you first have to understand that, as the virologist Dylan H. Morris explained in a great essay, what made SARS-CoV-2 so dangerous is not so much its intrinsic characteristics but the fact that it was novel, which means that nobody in the population had immunity against it.1 Indeed, while the debate about whether SARS-CoV-2 was “worse than the flu” or “just like the flu” dominated the early phase of the pandemic and to some extent is still ongoing, this question is not even well-posed because there is no such thing as the dangerousness of a virus simpliciter. The dangerousness of a virus is always relative to a particular context. This should be obvious if you consider the impact that the availability of effective treatments can have on how much damage a virus does. For instance, HIV was initially devastating because it invariably killed the people it had infected within a few years after symptoms onset, but thanks to the development of effective treatments infected people can now live a relatively normal life, at least in the developed world where people can afford such treatments. HIV has not become any less intrinsically dangerous, but it’s undoubtedly far less dangerous in societies where effective treatments are easily available.
In the case of SARS-CoV-2 though, the key contextual factor is what proportion of the population has immunity against it. Immediately after the emergence of the virus, the population was immunologically naive, which means that nobody had immunity against it beyond that conferred by the innate immune system against any pathogen.2 The amount of damage and disruption caused by a virus can differ wildly depending on whether the population in which it’s introduced is immunologically naive to it. This is because, when nobody in the population has immunity, 1) the virus spreads more easily and infects more people because everyone is susceptible to infection and 2) when people get infected they have a much higher chance of developing a severe form of the disease because their immune system does not yet have any weapons specifically tailored to fight this virus. So the same virus, with exactly the same intrinsic properties, can do vastly more damage in a population that is immunologically naive than in a population where everyone has immunity against it, either because they have previously been infected or because they have been vaccinated. That’s one of the reasons why entire indigenous communities in America were almost completely wiped out by pathogens brought by Europeans, even though people in Europe had been living with the same pathogens for centuries or even millennia and, while they were not by any means harmless to them, they didn’t threaten their existence.3
As more people get infected by SARS-CoV-2 or vaccinated against it, the virus will become endemic and continue to circulate following a seasonal pattern (because immunity whether acquired naturally or through vaccination is not 100% effective against infection and wanes over time), but the number of people who end up at the hospital or dead because of it will gradually decrease until we reach a sort of equilibrium.4 In some places, especially in developed countries where the vast majority of the population has already been vaccinated, this process is already well under way and you can see it on a simple chart:
This is probably also true in other regions of the world, where infections usually played a bigger role than vaccination, and eventually it will be true everywhere, including in places such as Australia and New Zealand that have mostly been able to keep the virus out so far but won’t be able to do it forever as the virus becomes endemic in the rest of the world. Obviously, it’s preferable to build up immunity through vaccination rather than infections, but eventually everyone will get to the same point. The virus will become endemic and virtually everyone will have some immunity against it, at which point it will be relatively harmless and no longer cause the kind of damage we have seen during the pandemic. The whole process will take a few years, but again it’s already well under way in some places and this is where everyone is headed, dreams of eradication notwithstanding.
In order to understand how this transition takes place and why the virus will be mostly harmless once it has become endemic and the population is no longer immunologically naive to it, I think it’s useful to work through a simple numerical example, which doesn’t purport to be a quantitatively accurate description of what is going to happen but can illustrate the process qualitatively and help people to grasp the underlying logic. Let’s consider a population of 10 million with 3 million people between 0 and 18 years old, 4 million people between 19 and 59 people and 3 million people 60 and over. Suppose that in that population a virus kills 0.05% of the people between 0 and 18 years old it infects, 0.2% of the people between 19 and 59 and 1% of the people 60 and over. Let’s also assume that, during the first year after it’s introduced in the population (which is initially immunologically naive to it), 25% of the population is infected and this doesn’t vary by age. In that case, we expect that during that year it will kill 25% * 3,000,000 * 0.05% = 375 people between 0 and 18 years old, 25% * 4,000,000 * 0.2% = 2,000 people between 19 and 59 years old and 25% * 3,000,000 * 1% = 7,500 people 60 and over died, for a total death toll of 9,875. That is a pretty sizable mortality, comparable to what many countries have seen during the first year of the COVID-19 pandemic, which given the assumptions I made should not come as a surprise to anyone.
Now let’s consider the same virus but in another population of 10 million or in the same population at a subsequent date where, because of vaccination and infections, the prevalence of immunity is only 25% among people between 0 and 18 years old, but 100% in the rest of the population.5 Let’s further assume that immunity is 80% effective against death and that effectiveness doesn’t vary with age, but that it’s not as effective against infection. Still, it offers some protection against infection, so the virus doesn’t spread as much as in a population where there is no immunity whatsoever. Let’s be more specific and assume that, over the course of a year, 15% of people between 0 and 18 years old, 10% of people between 19 and 59 years old and 5% of people 60 and over get infected.6 Finally, let’s assume that 75% of the children who get infected had no prior immunity, while 100% of the adults who get infected had some immunity since we have assumed that except for children everyone had immunity. In that case, we expect that 15% * 3,000,000 * (75% * 0.05% + 25% * (1 – 80%) * 0.05%) = 180 people between 0 and 18 years old, 10% * 4,000,000 * (1 – 80%) * 0.2% = 160 people between 19 and 59 years old and 5% * 3,000,000 * (1 – 80%) * 1% = 300 people 60 and over died, for a total death toll of 640. That’s only ~6.5% of the death toll in the immunologically naive population, yet by assumption the virus is exactly the same as before, but the population is no longer immunologically naive and this changes everything. For various reasons I won’t get into here, reality is far more complicated than this simplistic model, but it’s good enough to grasp the basic logic that governs the transition toward endemicity and get a pretty accurate idea of what is going to happen.7
Sooner or later, as a result of both infections and vaccination, virtually everyone will develop some immunity against SARS-CoV-2. This immunity will not always prevent infection, but even if someone who has been vaccinated or previously infected gets reinfected, they will typically develop only a mild form of the disease, because while still not perfect the protection against severe illness that immunity confers is better and doesn’t wane as quickly as protection against infection. Even the protection against severe illness will likely wane after a while, but this won’t really be a problem because, since immunity is much less effective against infection and new people are going to get born who are completely susceptible because they have never been infected yet and won’t be vaccinated, the virus will continue to circulate so most people will be reinfected every few years. Most people see that as a bug, but in a way, it may actually be a feature. Indeed, those reinfections will typically be mild because immunity protects well against severe illness, but they will update immunity and therefore ensure that, the next time someone is infected, this reinfection is also mild. As long as the virus is not eradicated, which as we have seen is not going to happen, we don’t want it to circulate too much, but we also don’t want it to circulate too little. Otherwise, too much time may elapse between two infections in the same person, in which case even the protection against severe illness conferred by immunity may have waned by the time they get reinfected.
Eventually most people will have a primary infection when they’re children, which is perfectly harmless and, together with subsequent infections, will protect them against severe illness later, when infection would be more dangerous if they didn’t have any immunity. Since once people have immunity, infections are generally mild, most people likely won’t even bother getting vaccinated because the probability of becoming seriously ill due to SARS-CoV-2 will be very small since 1) the risk of getting infected in the first place will be low because immunity still offers some protection against infection and the virus will circulate much less after it has become endemic and 2) even if they are infected they will typically be well protected against severe illness. Elderly people will be the exception because their immune system is compromised, so for them it will make sense to get a vaccine booster on a regular basis and I expect that it’s what most of them will do, as they already do against the flu. Once it has become endemic, which again will take a few years or even decades for the transition to be fully over, SARS-CoV-2 will become just another respiratory virus and will never cause the damages it has just wrought on us again. At last, it will have become “just like the flu”, except that it probably won’t be as bad as the flu if only because immunity will be more effective and longer-lasting.8 This may have already happened in the past with a coronavirus after the 1889-1891 “Russian flu” pandemic, which some now believe to have actually been caused by the emergence of HCoV-OC43, another human coronavirus that is now endemic and causes the common cold. It’s likely that SARS-CoV-2 will follow a similar path and end up being similarly harmless.
How I learned not to worry about variants and why you shouldn’t either
I have argued that, although SARS-CoV-2 is not going anywhere and that it wouldn’t be eradicated, things are looking up and that as the virus becomes endemic it would become mostly harmless. However, I know that presented with the optimistic picture I painted of what lays ahead of us, many people will react in disbelief because they think that emerging variants of the virus will get in the way of this quasi-idyllic scenario. Instead of seeing the wave of infections associated with the Delta variant as the last jolts of a pandemic on the way out as the transition toward endemicity takes place, they see it as a sign that, because new variants will keep emerging, we are going to be trapped in a never-ending cycle of waves of infections, each of them leaving scores of dead behind. Given that since the end of 2020 and the emergence of the Alpha variant in England, a wave of variantophobia has taken over the world, I can’t blame you if you worry that something like that might be true, but if that’s the case then I think you will feel much better after reading this section because the case against this variantophobia is very strong and we have every reason to believe that variants won’t prevent the scenario I described above from unfolding. First, before I say anything else, just taking another look at the chart about what just happened in England above should already assuage your worries somewhat, but there is more so please just bear with me for a little longer and I promise that you won’t regret it.
Variants are neither a new phenomenon nor something peculiar to SARS-CoV-2. Viruses constantly mutate and, as a result, variants of SARS-CoV-2 started to emerge long before the public became aware of that phenomenon a few months ago. While I do not doubt that mutations can result in different properties, as I have already explained previously, the picture is more complicated than what epidemiologists claim, especially when it comes to their claims about the advantage of transmissibility that, according to them, some variants enjoy. But the real concern people have about variants in the long-run is that they might evade pre-existing immunity, in which case we’d pretty much be back to square one. Indeed, the optimistic prediction I made about what is going to happen as the virus becomes endemic depends on the fact that, once everyone has acquired immunity against the virus, it will no longer kill a large number of people because immunity will ensure that it circulates less so fewer people will be infected and that even when someone is infected the infection will usually be mild. Obviously, if new variants emerge that can evade this immunity, this is not going to work and the pandemic will not end. But this is not going to happen and people who say otherwise are just talking nonsense.
In order to understand why, you must know a few things about how immunity works. Most people think of immunity as a black-or-white kind of thing: you either have it and you’re completely protected against both infection and severe illness or you don’t have it and you’re not protected against either. However, that is not how it works, the reality is more complicated. Immunity has several layers and comes in degrees. I have already noted that immunity against SARS-CoV-2 offered better protection against severe illness than against infection, but it’s even more complicated than that. For one thing, even if you have never been infected by SARS-CoV-2 and have not been vaccinated, it’s not true that you have no immunity against it. You have some immunity against it because your innate immune system is capable of fighting off even pathogens that you have never encountered. If this were not true, everyone who is exposed to SARS-CoV-2 would have died, but almost everyone survives and the overwhelming majority of people only have mild symptoms or no symptoms at all. It’s just that sometimes this innate immunity is not enough to clear the infection on its own before things get ugly, so it needs the adaptive immune system, which is responsible for mounting a more specific immune response to pathogens.
Unlike the innate immune system, which offers generic protection against pathogens, the adaptive immune system offers tailor-made protection against specific pathogens that it previously encountered. It relies mainly on two types of cells, B-cells and T-cells, that each play a different role, but in both cases they work by recognizing parts of proteins called epitopes expressed by the pathogen, which in the case of SARS-CoV-2 is a virus. B-cells have receptors that directly bind epitopes on the surface of the virus, then proliferate and create antibodies that can also bind those epitopes, which prevents the virus from infecting cells and helps other types of cells in the immune system to remove them. In the case of T-cells, on the other hand, recognition is a bit more indirect. Viral proteins are first broken up into short chains of amino acids called peptides inside cells that are called antigen-presenting cells (APCs).9 Those peptides are then bound to molecules known as the major histocompatibility complex (MHC) and the resulting MHC-peptides complexes are transported to the surface of the APCs where they are presented for recognition by T-cells.10 T-cells have receptors that bind different types of MHC-peptide complexes and, if they recognize one of them, they get activated and start going to work against the virus. This contributes to the immune response in various ways, but in particular sets in motion the process that will result in the destruction of the cells that have been infected by the virus.11 Here is a chart adapted from this paper that summarizes B-cell and T-cell epitope recognition:A key fact about both T-cells and B-cells is that, when they are activated, they don’t just set in motion a process that will help clear the infection currently ongoing, but also a process that will allow them to do that more quickly the next time they encounter the virus.
You’re probably wondering why I’m telling you about all that, but don’t worry, you’re about to find out. In the case of SARS-CoV-2, antibodies seem to be crucial to protect against infection, which makes sense because if there are still many antibodies that can neutralize the virus around when someone is exposed to the virus again, it won’t even have the opportunity to infect cells and replicate. However, several studies have found that the number of antibodies against SARS-CoV-2 wanes relatively quickly after vaccination or a natural infection, so often immunity can’t prevent infection. But as we have just seen, the immune response is not limited to antibodies, let alone to the antibodies against SARS-CoV-2 that are still around by the time someone is exposed to the virus again. Upon a second exposure with the virus, T-cells whose receptors bind peptides from SARS-CoV-2 will go to work again, but this time they’ll be able to do it more quickly. This will ensure that, even if infection couldn’t be prevented, it will be cleared before things take a turn for the worst. Thus, T-cells play a key role in preventing severe illness and, unlike antibodies, neither B-cells nor T-cells specific to SARS-CoV-2 seem to wane quickly. In fact, according to various studies (including one which found that T-cells specific to SARS-CoV-1 were still present in the blood of people who had been infected 17 years ago), they likely stick around for years. So even though protection against infection seems relatively short, immunity likely confers protection against severe illness for a long time. But won’t new variants find a way to evade this pre-existing immunity and make even the protection against severe illness it confers ineffective? No, they almost certainly won’t, and T-cells are the reason why.
Indeed, T-cells mount a particularly robust immune response because they target a much greater number of epitopes than antibodies, so even the virus mutates to prevent antibodies resulting from a previous infection to bind it, this is unlikely to work against T-cells because the entire viral proteome of the virus, i. e. the complete set of proteins expressed by the virus, would have to be different. But SARS-CoV-2 mutates pretty slowly, so although new variants regularly emerge and will continue to do so in the future, most peptides from the virus will remain the same and therefore T-cells will still be able to recognize them. Indeed, the peptides that are bound to MHC molecules and presented on the surface of antigen-presenting cells are very short chains of between 8 and 25 amino acids (depending on the class of MHC to which they are bound), so they are unlikely to change even as the virus mutates. Since it mutates slowly, it’s kind of as if the virus were trying to win the lottery by just buying a handful of tickets, each of them with a very low probability of winning the jackpot. If it bought 500 of them, the probability that one of them is a winning ticket may be reasonably high, but since it only buys 8 to 25 of them in each case it’s very low. Moreover, even if one amino acid changes, this is usually not enough to prevent T-cell receptors from binding, so in this case having a winning ticket does not even guarantee that the virus will actually pocket any money. Of course, it will sometimes happen, but T-cells target hundreds of epitopes from SARS-CoV-2, so it won’t really make a difference to the overall immune response they mount against the virus. T-cells just take the recommendation that you shouldn’t put all your eggs in the same basket very seriously.
This looks fine in theory, but reality has a way of frustrating our theoretical expectations, so does it also work in practice? Yes, it does, it works exactly as theory predicts. A recent study examined the impact of SARS-CoV-2 variants on T-cell reactivity and found that, depending on the type of receptor, between 93% and 97% of the hundreds of previously identified T-cell epitopes were not affected by mutations in the variants of concern. Now, all epitopes do not contribute equally to the immune response mounted by T-cells, so in theory it could be that while only a handful of them were affected by mutations in variants of concern, they happened to be epitopes that were disproportionately involved in the T-cell response. But the authors checked and found that fully conserved epitopes accounted for on average 91.5% of the response, so this isn’t the case. Again, keep in mind that even for the handful of epitopes that were affected by mutations, it doesn’t mean that receptors from a previous infection are no longer capable of recognizing them. In any case, the study also found there was no statistically difference in reactivity of T-cells from people who had acquired immunity against the virus, whether it was through vaccination or a natural infection. It doesn’t mean that, had the sample been larger, a statistically significant difference wouldn’t have been found, but it means that at worse the loss of reactivity was small and possibly non-existent, which again is exactly what we’d expect based on the theoretical considerations. It may be that, although T-cells target hundreds of epitopes and SARS-CoV-2 is mutating slowly, after a long enough period of time it will have mutated enough that T-cells won’t be able to mount a strong enough immune response to protect against severe illness. But remember that SARS-CoV-2 is going to continue to circulate and that people will likely get reinfected every few years, so their immunity will be updated when they are, ensuring that any subsequent infections will also be mild.
But there is another reason almost nobody is talking about why it’s unlikely that we’ll see substantial immune evasion with T-cells. As I explained above, T-cells don’t recognize epitopes directly on the surface of the virus, but rather bind complexes formed by MHC molecules and peptides on the surface of antigen-presenting cells. Now, different MHC molecules can bind different peptides, which are then presented for recognition to T-cell receptors. As it happens, the region of the human genome that is responsible for the production of MHC molecules is the most polymorphic in the entire human genome, which means that even in the same population different individuals usually have different MHC molecules that can bind different epitopes from the virus before presenting them to T-cell receptors on the surface of antigen-presenting cells. This fact has been confirmed in the case of SARS-CoV-2 by another study that identified potential T-cell epitopes from the virus and used computational methods to predict their binding affinity with the MHC molecules produced by the different variants of the genes that code for them in human populations. The authors found there was significant variation in the epitopes derived from SARS-CoV-2 involved in T-cell response both across individual within the same population and between populations, although this variation wasn’t predicted to affect the overall level of response across individuals or populations.12 This is very important because it means that, even if the virus acquired mutations that allowed it to evade T-cell immunity in one individual or population, it typically wouldn’t help it evade T-cell immunity in another individual or population, which makes T-cell immune evasion even more unlikely.
The bottom line is that, if you’re the virus, T-cells are your worst nightmare. Getting ahead of antibodies is pretty easy and some variants of concern already do it to some extent, but T-cells are a completely different story and will be a much tougher nut to crack for the virus. As we have seen, we have very good theoretical and empirical reasons to expect that, in the war between the virus and T-cell immunity, not only is the latter going to win but it won’t even break a sweat doing it. It’s important to understand that, in that respect, SARS-CoV-2 is no different than other viruses and other viruses also have a hard time dealing with T-cell immunity. Indeed, as the authors of the study that examined the impact of SARS-CoV-2 variants on T-cell reactivity note, immune evasion at the level of T-cell response has never been reported for acute respiratory infections. People worry about variants because they hear that antibody response is not as effective against them, so they imagine that eventually another variant will emerge against which immunity will be completely ineffective, but that’s because they don’t know that antibodies are just one part of the immune response against SARS-CoV-2. Immunity has another layer depending on T-cells and, not only has this layer remained unaffected by mutations of the virus so far, but as we have just seen we have very good reasons to think it will continue to be true in the future.
As I noted above, it’s likely that SARS-CoV-2 will follow a trajectory similar to that of the other human coronaviruses (which are already endemic), so it’s particularly interesting to know that what I’m predicting for SARS-CoV-2 is exactly what is already happening with those human coronaviruses. A recent study examined the recent evolution of HCoV-229E, one of the four human coronaviruses that are already endemic, and found that its spike, the protein that allows the virus to enter cells and infect them, had undergone several mutations between 1984 and 2020. They used sera collected on recovering patients at various points during that period to test how well the antibodies they contain were able to bind reconstructed spikes of the virus from 1984, 1992, 2001, 2008 and 2016. What they found is that antibodies in sera collected at one date were able to find effectively the spikes that were found on HCoV-229E before that date, but not or not very effectively the spikes that were found on the virus after that date, which shows that HCoV-229E had mutated to evade antibody binding, which is already what we’re seeing in SARS-CoV-2. But HCoV-229E remained mostly harmless during that period, which is presumably because while people’s antibody response against it became less efficient due to mutations in the spike, T-cell immunity remained largely unaffected. This is exactly what we’re seeing with SARS-CoV-2 so far and we have every reason to believe that it will continue to be true in the future. The only difference is that, in the case of HCoV-229E, nobody bothers naming the variants and people aren’t freaking out because they think immunity will stop working against them. Again, SARS-CoV-2 is just another respiratory virus, what made it so devastating is that it was novel.
SARS-CoV-2 is not going anywhere
Some people insist that we can’t “live with the virus” and that we must therefore pursue a policy of eradication. They often draw a parallel with smallpox and say that we should do the same thing with SARS-CoV-2 that we did with that virus, which after plaguing mankind for thousands of years was finally eradicated in 1980. This parallel is extremely misleading though, because smallpox differs from SARS-CoV-2 in very important ways, which made eradication possible though difficult in the case of the former but make it very unlikely in the case of the latter. Before I get into that, it’s worth noting that to date only two infectious diseases have ever been successfully eradicated (smallpox in humans and rinderpest in cattle), which speaks to how difficult this sort of enterprise is. This is not for lack of trying, as several other infectious diseases have been targeted for eradication, but those efforts have not succeeded yet. Polio seems on the verge of eradication and probably will be eradicated soon, but isn’t yet. Even in the case of smallpox, eradication took decades. You might take this to suggest that, while SARS-CoV-2 will not be eradicated overnight, we might pull it off eventually if we really commit to it. But I don’t think it’s going to happen because again SARS-CoV-2 is very different from the viruses that cause smallpox or polio.
First, while I think there is no doubt that vaccines against SARS-CoV-2 protect against infections and not just severe disease (as we have seen above), I think it’s equally clear that the protection it offers against infection is far from perfect and that people can get infected even if they have been vaccinated. There is also growing evidence that, while it does not disappear almost immediately as some people had initially suggested based on weak evidence, the protection against infection conferred by vaccination is waning relatively quickly. As this study showed, the same thing is true for the immunity against endemic human coronaviruses induced by natural infection, so this is not particularly surprising. According to the COVID-19 Infection Survey, based on a random sample of the population in the United Kingdom, more than 90% of people had antibodies against SARS-CoV-2 in June, but it didn’t prevent a gigantic third or fourth wave (depending on how you’re counting) from ripping through the country in July. The same thing just happened in Iceland, where more than 90% of the population over 16 has received at least one dose of vaccine. As we have seen, this is not really a problem because thanks to vaccination and naturally acquired immunity mortality remained low, but it suggests that even mass vaccination within a short period of time cannot stop the virus from circulating. The vaccine against smallpox, on the other hand, probably confers lifelong protection against infection and the same thing seems to be true about naturally acquired immunity. Basically, in order to get rid of smallpox, we “just” needed to vaccinate everyone in their childhood and that was it. The same thing is true with polio.
So this means that, in order to eradicate SARS-CoV-2, we’d have to vaccinate the entire population every year for several years in a row and even that would probably not be enough.13 That’s a much larger effort than what we had to do to get rid of smallpox, yet even that comparatively simple endeavor took decades. Who can seriously believe that we’ll be able to sustain that effort for the years or even decades that it would take to eradicate the virus, when we aren’t even able to do it in the middle of a pandemic that just killed millions of people? This is a pipe dream, it will never happen. Indeed, convincing or coercing people to get vaccinated is going to become even harder, because as I have explained the virus will be mostly harmless once it has become endemic. If you think it’s hard to convince people to get vaccinated or politically difficult to coerce them to do so while people are dropping dead by the thousands, which it most certainly is, wait until the mortality caused by SARS-CoV-2 is divided by a factor of 20 or something. It’s pointless and wasteful to pursue a policy that has no realistic chance of succeeding, but that’s exactly what people who are calling to eradicate SARS-CoV-2 are doing. Not that it will make any difference, to be clear, because the same reasons that make this project a fantasy will ensure that calls to carry it out will remain unanswered.
Again the comparison with smallpox or even polio is extremely misleading here. Smallpox is one of the most lethal pathogens in history and has probably killed hundreds of millions of people in the last 100 years of its existence alone. It’s painfully obvious that the incentives are completely different in the case of SARS-CoV-2. Even with polio, whose infection fatality rate is similar to SARS-CoV-2, the incentives are very different because it mostly kills or maims children. Does anyone really expect that people are going to be as motivated to eradicate a virus that mostly kills elderly people as they are to get rid of a virus that kills or paralyzes children? Moreover, as I already noted, in the case of polio, you just have to administer a few shots to people when they’re very young children and you’re done with it. The comparison of SARS-CoV-2 with other pathogens can be illuminating in some cases, but comparing it to smallpox or even polio to suggest that we could eradicate it and that it’s a realistic possibility is extremely misleading. Even if we granted for the sake of the argument that it could be done if we committed enough resources to the effort, it’s totally unrealistic to expect that we ever will, because the incentives aren’t right.14
There are other differences between SARS-CoV-2 and smallpox or even polio that make it far more difficult to eradicate the former. In particular, smallpox and polio only infect humans, but SARS-CoV-2 can also infect animals and frequently does. While the evidence of animal-to-human transmission is so far very limited, I think it’s mostly because the studies that have found evidence that animals could be infected by SARS-CoV-2 were not designed to answer that question. If the virus becomes endemic in some animal populations that are frequently in contact with humans, then even if we somehow managed to temporarily eradicate it from human populations, animals would just reintroduce it and we’d be back to square one. At least one animal reservoir has already been found in the white-tailed deer population in the US, so this isn’t a purely theoretical worry. What this means is that, in order to permanently eradicate SARS-CoV-2 from human populations, we’d probably have to vaccinate wild animals. This can be done and has been done in some countries such as France, where a program to vaccinate some wild animals against rabies was undertaken, but it just makes eradication even more difficult and costly, which in turn makes it even more unlikely that we’ll even try, let alone succeed.
The pandemic is on its way out, but SARS-CoV-2 is here to stay. Fortunately, as everyone develops immunity to it (whether through vaccination or natural infection), it will soon no longer be a major problem anymore. The virus will continue to circulate, but much less than during the pandemic and, even when people are infected, the infection will typically be mild. In the future, almost everyone will get infected for the first time during their childhood, which is harmless and will protect them against severe illness when they are reinfected.15 The virus will continue to mutate and some of those mutations will favor immune evasion, but while this will allow it to infect people who have already been infected or vaccinated more easily, immunity should continue to protect against severe forms of the disease, thanks in particular to the role played by T-cells. This is likely what happened with other human coronaviruses, which are already endemic and typically cause a cold in the people they infect. To the extent that immune evasion occurs, it will be very gradual and the fact that most people will be infected every few years will update their immunity, ensuring that subsequent reinfections will also be mild. The most vulnerable people, whose immune system doesn’t work very well and could use some help to be ready in case of infection, can get a vaccine booster from time to time. The virus will still kill people, as the flu does, but it will never cause the same amount of disruption again. The hardest part of what lays ahead may be to convince people who have been traumatized by the pandemic that it’s over and that restrictions are no longer necessary.
P. S. I realize that, while it doesn’t exactly say that, this post makes it sound as though the only reason why protection against infection appears to have been waning is that new variants with mutations in the spike that allow them to prevent antibodies from binding have emerged, so to be clear that’s not what I’m saying. I was focusing on immune evasion, because that’s what people seem most worried about, but another reason why protection against infection is probably waning is that antibody levels progressively fall after infection. Moreover, as someone pointed out to me, so does the number of T-cells specialized against SARS-CoV-2 and I’m sure the same thing is true with B-cells, so as time goes by it also takes longer for the adaptive immune system to mount a response upon exposure to the virus. I also didn’t mean to suggest that mutations in the spike make antibodies completely inefficient. The point I wanted to make is just that, even if a variant is able to evade humoral immunity to a large extent, T-cell immunity should still work just fine against it and eventually the immune system should be able to mount a very effective response to infection, even if the fact that T-cell levels also wane means that it will take longer as the time since the last infection increases.
1As some studies suggest, there was probably some cross-immunity due to prior exposure to seasonal human coronaviruses, so this claim is not exactly true, but clearly this immunity was very limited.
2Biologists make a distinction between the innate immune system and the adaptive immune system. The former offers generic protection against pathogens that invade the body and can effectively deal with most of them, while the latter offers protection against specific pathogens that have been previously encountered. As I noted above, there was probably some adaptive immunity against SARS-CoV-2 in the population due to the similarity of parts of the proteins expressed by the virus with those of endemic human coronaviruses, but again it was very limited.
3Another reason is that natural selection had probably favored alleles that protect against those pathogens in Europeans precisely because they had lived with them for so long, whereas this was not the case in America where indigenous populations had separated from other human populations before the emergence of those diseases, which probably occurred during and after the neolithic when animals were first domesticated.
4The notion of endemic equilibrium has a precise mathematical definition in epidemiological models, but while those models may be useful to describe some aspects of this process in a stylized manner, I think they bear little connection to reality and use the term in a more informal sense.
5This is the kind of situation you would expect in a population where the virus has become endemic, almost everyone is infected for the first time during their childhood, immunity wanes over time but people get reinfected or vaccinated every few years.
6This is the kind of situation you would expect if old people got vaccinated regularly because they know they are vulnerable. You would expect the virus to circulate more among children since, by assumption, more of them are susceptible to infection.
7If you want to see a more realistic attempt at modeling the transition to endemicity, which tries to predict how long it will take depending on factors such as how fast the protection against infection conferred by immunity wanes and the basic reproduction number of the virus, I encourage you to read Lavine et al. (2021). I wouldn’t take very seriously their quantitative estimates, because the model still ignores many complications and the specific results are sensitive to various semi-arbitrary assumptions they make, but there is every reason to think their qualitative conclusions, which are consistent with the prediction I make below about what is going to happen once SARS-CoV-2 has become endemic, are correct because they just rest on the basic logic I have just explained.
8Indeed, influenza mutates faster than SARS-CoV-2 due to the absence of a similar proofreading mechanism during replication and because it has a segmented genome that makes recombination between various strains easier, which makes it harder for immunity to clear infection and explains why vaccines against the flu quickly become obsolete.
9The terminology can be a bit confusing, so it may be useful to clarify it. Epitopes are the parts of viral proteins that are recognized by the adaptive immune system, whether they are still part of the protein when this recognition takes place or have been broken up and are no longer part of it. In the case of B-cells, they are recognized directly on the protein that is still intact on the surface of the virus, but in the case of T-cells this recognition takes place after the viral proteins have been broken up into peptides. So peptides can be epitopes when they are presented on the surface of APCs for recognition by T-cells, but epitopes need not be peptides and peptides need not be epitopes.
10There are different classes of MHC molecules that are found on different kinds of APCs and are recognized by different types of T-cells, but this is not important for what I’m trying to explain.
11B-cells are APCs and therefore present MHC-peptide complexes to T-cells, which in turn stimulate the proliferation of B-cells specific to the relevant peptides and the production of antibodies that can bind them directly on the surface of the virus, so T-cells and B-cells are not entirely distinct parts of the immune system but interact in complex ways to produce the immune response.
12This result still held when they looked at potential T-cell peptides derived from individual proteins expressed by the virus rather than the entire viral proteome, so even if peptides derived from specific proteins are more important to the T-cell response than others, this response will still rely on different epitopes in different individuals and different populations. In particular, this is true for epitopes derived from the spike protein, which is the one used by the currently available vaccines to induce immunity.
13Perhaps this will change as new, more effective vaccines are developed, but I wouldn’t hold my breath, especially since as I have argued SARS-CoV-2 is going to become far less dangerous, so pharmaceutical companies will have less incentives to invest money into research and development for better vaccines against it.
14You may think that, although eradicating SARS-CoV-2 would be extremely costly and difficult, it would still be cost-effective given the expected death toll of COVID-19 in the long-run and you may even be right despite the fact that it’s going to become far less dangerous once it’s endemic. But this wouldn’t change the fact that it’s almost certainly not going to happen because, as we have seen during the pandemic, decision-makers are hardly utility maximizers. Thus, when I claim that eradication of SARS-CoV-2 is not desirable, I’m not committing myself to the view that, even if people were perfectly rational, such a policy wouldn’t pass a cost-benefit test (although I think it probably wouldn’t), but only to the weaker claim that it wouldn’t in the actual world because the lack of incentives to pursue this policy lowers the probability of success and increases the cost.
15At the moment, many people want to vaccinate their kids, but I doubt it will still be the case in a few years when the panic induced by the pandemic has subsided and people have realized that SARS-CoV-2 is harmless to children.
Authors: Alberto Mantovani, M.D., and Mihai G. Netea, M.D.
Innate immunity is mediated by different cell types and cell-associated or fluid-phase pattern-recognition molecules and plays a key role in tissue repair and resistance against pathogens.1 Exposure to selected vaccines, such as bacille Calmette–Guérin (BCG) or microbial components, can increase the baseline tone of innate immunity and trigger pathogen-agnostic antimicrobial resistance (known as trained innate immunity). Such training is directly relevant to resistance against infectious diseases, including Covid-19. A recent study by de Laval et al.2 pinpoints a driver of durable innate immune memory conferred by myeloid cells (monocytes, macrophages, and neutrophils).
Myeloid cells are central players in innate immunity: they produce effector molecules and contribute to the activation, orientation, and regulation of adaptive immune responses. Diversity and plasticity are fundamental properties of myeloid cells, particularly macrophages. To some extent, these properties are imprinted through ontogenetic origin (embryonal vs. adult bone marrow), but they are also influenced by environmental cues in the tissue. Moreover, in response to microbial molecules, metabolic products, or cytokines, macrophages increase effector function (“activation”), are primed for short-term responses (“priming”), or become unresponsive (“tolerance”). Microbial components can also cause long-term imprinting (“training”) of innate immunity and myeloid-cell function (Figure 1).3 (This type of imprinting is distinct from genomic imprinting whereby methyl groups are added to DNA in or near specific genes.)
Authors: Alessandro Sette1,2 and Shane Crotty1,2,* 1Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA 2Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037, USA
SUMMARY The adaptive immune system is important for control of most viral infections. The three fundamental components of the adaptive immune system are B cells (the source of antibodies), CD4+ T cells, and CD8+ T cells. The armamentarium of B cells, CD4+ T cells, and CD8+ T cells has differing roles in different viral infections and in vaccines, and thus it is critical to directly study adaptive immunity to SARS-CoV-2 to understand COVID-19. Knowledge is now available on relationships between antigen-specific immune responses and SARS-CoV-2 infection. Although more studies are needed, a picture has begun to emerge that reveals that CD4+ T cells, CD8+ T cells, and neutralizing antibodies all contribute to control of SARS-CoV-2 in both non-hospitalized and hospitalized cases of COVID-19. The specific functions and kinetics of these adaptive immune responses are discussed, as well as their interplay with innate immunity and implications for COVID19 vaccines and immune memory against re-infection.
Coronavirus disease 2019 (COVID-19), caused by the novel human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Hu et al., 2020), is a serious disease that has resulted in widespread global morbidity and mortality.
Our understanding of SARS-CoV-2 and COVID-19 has rapidly evolved during 2020. As of December 2020, the United States has experienced >300,000 deaths, winter cases are rising exceptionally fast, and the first interim phase 3 vaccine trial results have been reported. The scientific advances in understanding SARS-CoV-2 and COVID-19 have been extraordinarily rapid and broad, by any metric, which is an amazing testament to the commitment, creativity, collaboration, and expertise of the international scientific community, both in academia and industry, under extremely challenging conditions. This article will review our current understanding of the immunology of COVID-19, with a primary focus on adaptive immunity.
The immune system is broadly divided into the innate immune system and the adaptive immune system. Although the adaptive and innate immune systems are linked in important and powerful ways, they each consist of different cell types with different jobs.
The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells (Figure 1). B cells produce antibodies. CD4+ T cells possess a range of helper and effector functionalities. CD8+ T cells kill infected cells. Given that adaptive immune responses are important for the control and clearance of almost all viral infections that cause disease in humans, and adaptive immune responses and immune memory are central to the success of all vaccines, it is critical to understand adaptive responses to SARS-CoV-2.
ONE INTEGRATED MODEL OF IMMUNE RESPONSES TO SARS-CoV-2
This review first presents a working model of immune responses to SARS-CoV-2, to provide an overarching context, and then the review explores individual compartments and immunological facets of adaptive immunity to SARS-CoV-2 in greater detail. Importantly, this is an evolving model and should not be accepted as definitive; instead, it provides a reference point for interpreting much of the available data in the literature and to identify knowledge gaps that may provide directions for future studies.
Determining the duration of protective immunity to infection by SARS-CoV-2 is crucial for understanding and predicting the course of the COVID-19 pandemic. Clinical studies now indicate that immunity will be long-lasting.
Generating immunity against the SARS-CoV-2 coronavirus is of the utmost importance for bringing the COVID-19 pandemic under control, protecting vulnerable individuals from severe disease and limiting viral spread. Our immune systems protect against SARS-CoV-2 either through a sophisticated reaction to infection or in response to vaccination. A key question is, how long does this immunity last? Writing in Nature, Turner et al.1 and Wang et al.2 characterize human immune responses to SARS-CoV-2 infection over the course of a year.
There is ongoing discussion about which aspects of the immune response to SARS-CoV-2 provide hallmarks of immunity (in other words, correlates of immunological protection). However, there is probably a consensus that the two main pillars of an antiviral response are immune cells called cytotoxic T cells, which can selectively eliminate infected cells, and neutralizing antibodies, a type of antibody that prevents a virus from infecting cells, and that is secreted by immune cells called plasma cells. A third pillar of an effective immune response would be the generation of T helper cells, which are specific for the virus and coordinate the immune reaction. Crucially, these latter cells are required for generating immunological memory — in particular, for orchestrating the emergence of long-lived plasma cells3, which continue to secrete antiviral antibodies even when the virus has gone.
Immunological memory is not a long-lasting version of the immediate immune reaction to a particular virus; rather, it is a distinct aspect of the immune system. In the memory phase of an immune response, B and T cells that are specific for a virus are maintained in a state of dormancy, but are poised to spring into action if they encounter the virus again or a vaccine that represents it. These memory B and T cells arise from cells activated in the initial immune reaction. The cells undergo changes to their chromosomal DNA, termed epigenetic modifications, that enable them to react rapidly to subsequent signs of infection and drive responses geared to eliminating the disease-causing agent4. B cells have a dual role in immunity: they produce antibodies that can recognize viral proteins, and they can present parts of these proteins to specific T cells or develop into plasma cells that secrete antibodies in large quantities. About 25 years ago5, it became evident that plasma cells can become memory cells themselves, and can secrete antibodies for long-lasting protection. Memory plasma cells can be maintained for decades, if not a lifetime, in the bone marrow6.
The presence in the bone marrow of long-lived, antibody-secreting memory plasma cells is probably the best available predictor of long-lasting immunity. For SARS-CoV-2, most studies so far have analyzed the acute phase of the immune response, which spans a few months after infection, and have monitored T cells, B cells and secreted antibodies7. It has remained unclear whether the response generates long-lived memory plasma cells that secrete antibodies against SARS-CoV-2.
Updated Aug. 6 with CDC analysis of Kentucky (unvaccinated Kentuckians had “2.34 times the odds of reinfection“ compared with fully vaccinated) and national analysis in Israel (vaccinated Israelis were 6.72 times more likely to get infected after the shot than after natural infection). More below.
Sen. Lindsey Graham (R-S.C.) became one of the latest high-profile figures to get sick with Covid-19, even though he’s fully vaccinated. In a statement Monday, Graham said it feels like he has “the flu,” but is “certain” he would be worse if he hadn’t been vaccinated.
While it’s impossible to know whether that’s the case, public health officials are grappling with the reality of an increasing number of fully-vaccinated Americans coming down with Covid-19 infections, getting hospitalized, and even dying of Covid. The Centers for Disease Control (CDC) insists vaccination is still the best course for every eligible American. But many are asking if they have better immunity after they’re infected with the virus and recover, than if they’re vaccinated.
Increasingly, the answer within the data appears to be ”yes.”
Why does CDC seem to be “ignoring” natural immunity?
In fact, some medical experts have said they’re confounded by public health officials’ failure to factor natural and virus-acquired immunity into the Covid equation. Public and media narratives often press the necessity of “vaccination for all,” chiding states where vaccination rates are lowest. And they use vaccination rates and Covid case counts as inverse indicators of how safe it is in a particular state: high vaccination rate = high safety; high case counts = low safety (they claim).
However, vaccination rates alone tell little about a population’s true immune-status. And where high Covid case counts occur, it ultimately means a larger segment of that community ends up better-protected, vaccines aside. That’s according to virologists who point out that fighting off Covid, even without developing any symptoms, leaves people with what’s thought to be more robust and longer-lasting immunity than the vaccines confer.