Postinfectious Immunity After COVID-19 and Vaccination Against SARS-CoV-2

Abstract

Early results suggest that SARS-CoV-2 vaccines are highly effective for the prevention of COVID-19. Unfortunately, until we can safely, rapidly, and affordably vaccinate enough people to achieve collective immunity, we cannot afford to disregard the benefits of naturally acquired immunity in those, whose prior documented infections have already run their course. As long as the vaccine manufacturing, supply, or administration are limited in capacity, vaccination of individuals with naturally acquired immunity at the expense of others without any immune protection is inherently inequitable, and violates the principle of justice in biomedical ethics. Any preventable disease acquired during the period of such unnecessary delay in vaccination should not be overlooked, as it may and will result in some additional morbidity, mortality, related hospitalizations, and expense. Low vaccine production capacity complicated by inefficiencies in vaccine administration suggests, that vaccinating preferentially those without any prior protection will result in fewer natural infections more rapidly.

Introduction—Equitable Distribution of Vaccines

Many experts have raised concerns about equitable SARS-CoV-2 vaccine distribution around the globe and recommended preferential vaccination for those at the highest risk of dying from COVID-19 and health care workers (15,40). Safe vaccination of all those who need and want it is absolutely necessary, however, the order matters. Vaccine efficacy in the population and true equity of vaccine distribution strategies will suffer, if we fail to account for the proven protection afforded to those who already cleared a confirmed symptomatic COVID-19 (confirmed by PCR or another highly specific test) (csCOVID-19) (45).

As long as the vaccine supply or administration remain limited in capacity, vaccination of individuals with postinfectious immunity at the expense of others without any immune protection is inherently inequitable, and violates the principle of justice in biomedical ethics (4). Any preventable disease acquired during the period of such unnecessary delay in vaccination should not be overlooked, as it may and will result in some additional morbidity, mortality, and related hospitalizations and expense.

Naturally Acquired Protection—Once We Involuntarily Have It

There are important unproven assumptions regarding natural versus vaccine-generated SARS-CoV-2 immunity. One such assumption asserts that we cannot rely on immunity acquired by natural infection, because such strategy “is lethal to many” and that it is not effective (28). Such statements need to be qualified by more detail regarding who lacks protection and why. Scientific uncertainty is hard to disclose, especially in the face of exaggerated skepticism and opposition toward public health measures, including vaccination, which have become extraordinarily pervasive around COVID-19 (7). However, hyperbolic phrasing can be counterproductive (58) and is not supported by the current scientific evidence, which reasonably relies on the natural protection (currently for 90 days) (27).

In fact, the proportion of individuals with csCOVID-19 reinfection appears to be low. Current literature lists only a small number of confirmed and suspected COVID-19 reinfection cases (5,18,20,30,39,44,52,53,56) out of over 125 million cases reported by The Johns Hopkins COVID-19 tracker in March 2021 (12). A minority of the 66 properly confirmed cases [as of March 25th, 2021 (5)] had a more symptomatic second course.

Some characteristics of COVID-19 suggest that formation of a reservoir causing virus persistence seems likely and that reactivation rather than reinfection can be responsible for a number of the “suspected” reinfections, and we do not know how subsequent vaccinations would affect this (48). It is possible that interferon response deficiency (3,61), and other immunological insufficiencies (59) in some individuals could be responsible for poor COVID-19 outcomes, and there is no evidence to say that individuals with similar immunological make-up would not suffer similar outcomes if exposed after vaccination as well.

Natural infection presents all the necessary immunogenic targets, which may prove more secure against some mutation-associated escapes. It is also possible that complete antigen presentation may prime a more complete cellular immunity, although, to our knowledge, this has not been sufficiently explored (19).

Recent studies reported that SARS-CoV-2-specific CD4 and CD8 T cell-coordinated activity was strongly associated with milder disease but the presence of neutralizing antibodies at various levels was not (31,46). Additionally, cellular reactivity does not appear to be noticeably affected by the antibody escape mutants (51). Cellular immunity may thus be more important and more durable than the antibody response, especially given that some who naturally cleared SARS-CoV-2 infection did so without high, or even without detectable levels of neutralizing antibodies.

However, the presence of neutralizing antibodies with sufficiently high titers is thought to be the only mechanism capable of truly sterilizing immunity, although only when supported by coordinated cellular immunity, without which viral clearance is unlikely to occur (13). The implication being that lower levels of sterilizing antibodies together with functional cellular immunity could be protective from severe disease while still allowing for at least a limited transmission potential [10–20 × less frequent transmission has been reported from asymptomatic vs symptomatic individuals (35)].

In relevant recent animal experiments (rhesus macaques), natural infection in two trials provided similar level of protection (9,14) as did three different types of vaccine in trials with a similar design (measured by the magnitude of reduction in viral shedding, and clinical picture plus lung pathology) (10,55,60).

It is worth mentioning that some individuals who cleared natural infection with SARS-CoV-2, especially the younger ones, may not have a detectable level of antibodies in the serum, although they may have a high level of mucosal antibodies, capable of virus neutralization (8). How much of an impact robust oro- and nasopharyngeal mucosa-associated antibodies can have on the viral entry into the cells after exposure is not sufficiently clear at this point. And while it does not appear that this would be a significant problem for a vaccine-derived protection, given the nonsterilizing immunity in both natural and vaccine-derived protection—it may have an impact on the amount of viral shedding after an exposure.

Highly Effective Vaccines So Far

Moderna's and Pfizer-BioNTech's mRNA vaccine trials report a ∼95% efficacy (38,43). Slightly lower efficacy (62–90%) was reported by Oxford/Astra Zeneca's adenovirus-based vaccine (57). The follow-up of individuals in these trials has been considerably shorter as compared with the many individuals naturally infected since the beginning of the pandemic, which also means that these data are looking at the best possible scenario—since early on is when the immune response is the strongest (Paul Offit in podcast with JAMA editor Howard Bauchner) (11).

Furthermore, the incidence rate, which was relatively low in both mRNA vaccine trials at 0.7–0.85%, instead of the expected ∼3%, may suggest that the participants were from a group with higher health literacy, potentially introducing some bias through better utilization of other protective measures (diligent masking, distancing, and overall avoidance of high-risk situations).

These measures, by design, result not only in complete prevention of exposure but also along the same spectrum—when exposures do occur, they may be associated with a lower infectious inoculum and thus lower severity of resulting disease, including asymptomatic shedding (not measured in mRNA vaccine trials) (17).

Making the Most Out of What We Have

The rigorous follow-up in vaccine trials is, of course, unmatched by the reporting of naturally occurring cases, although any severe reinfections in previously mildly ill individuals would have been broadly reported, specifically in those millions of people with csCOVID-19. Furthermore, the possibility of viral reactivation instead of reinfection is only now starting to enter the conversation. Considering these facts, it is highly unlikely that the number of reinfections would reach even 1% (∼1,250,000) of csCOVID-19 tracked as of March 2021, perhaps excluding completely asymptomatic reinfections whose count is simply unknown.

It is possible that broader immunogenicity is responsible for severe physiological phenomena accompanying natural COVID-19 illness—such as thromboembolism (42) and its sequalae (54), vascular inflammation (50), “long-covid” (41), which seem to be immunologically mediated and can be minimized or completely avoided with vaccination before natural infection. It is unclear, however, whether these problems would be mitigated or exacerbated by early vaccination of those, whose symptomatic (more immunogenic) infection has already run its course.

Even if a concentrated presentation of the spike protein has the capacity to overcome some of the durability problems with acquired immunity or, perhaps also refocus the immune response in post-COVID complications, this would not play any meaningful role if such vaccination was delayed for a brief scientifically defined period in people with recent csCOVID-19.

One study reported that the presence of neutralizing antibodies specifically was not associated with disease severity, while SARS-CoV-2-specific CD4 T cells' association was clear (46). Cellular immunity may thus be more important and more durable than the antibody response, especially given that some who naturally cleared SARS-CoV-2 infection did so without high, or even detectable levels of neutralizing antibodies, whereas some with high antibody titers but lack of accompanying cellular immunity coordination suffered extremely poor outcomes.

From this perspective, it is hard to reconcile why some authorities very clearly recommend postponing vaccination by 3 months in people who received ∼600 mL of somebody else's plasma (or a dose of monoclonal antibodies), while merely acknowledging that people with ∼2,500 mL of their own convalescent plasma with a primed cellular immunity as a bonus merely “may” consider a similar delay (26,27).

Saving Resources Equals Saving Lives

This is not about whether we can engineer a better immune protection against COVID-19. Uniform dosing and safer immune response make these vaccines suitable for everyone lacking immune protection, and also for those whose protection may be insufficient due to low inoculum exposure or due to waning over time. However, if SARS-CoV-2 is indeed capable of persistence (48) with a possibility of future reactivations—preventing reservoir formation by preferentially vaccinating completely unexposed individuals would seem much more important. Discounting the obvious, although imperfect, efficacy of natural protection is highly impractical in a world drowning in COVID-19-related lockdowns and concerns about the equitable distribution of vaccines.

In a recent study documenting incidence of SARS-CoV-2 infection in English health care workers divided by antibody status over 6 months, the odds ratio for seropositive versus seronegative patients was 0.11 (34). Additionally, a large Danish study, also showing ∼80% protection in all but those >65 years of age (47%), also showed that this effect persisted in a follow-up lasting >7 months (22). Two more very large studies, from the US and Qatar showed even more impressive—roughly 90% protection (23,1). Perhaps most important, Hall et al. reported 84% protection from any infection, including asymptomatic form, which therefore would prevent the possibility of further spread by convalescents by at least the same amount (21). Within these studies, vaccinating the seropositive health care workers would have been the equivalent of revaccinating someone who just got the Oxford/Astra-Zeneca's ChAdOx1 vaccine (57) in the face of a vaccine shortage.

We are skeptical about not taking into account all those who are naturally protected when allocating the available vaccines. Even with the additional vaccines being approved in the near future, it does not seem that there will be enough, quickly enough (49)—any duplicity in immunization, especially early on, would not help with timely development of herd immunity (2). At the current growth rate, would it not be helpful to vaccinate >100 million additional people if we prioritized those without prior csCOVID-19?

If slowing down a rapidly growing pandemic is a solid argument for removing hurdles from the road to collective (herd) immunity, then not wasting time and limited resources on double immunization is part of the solution.

Proposed Solution

We suggest mathematical modeling based on the goals and associated prioritization of vaccine allocation as outlined by the Centers for Disease Control and Prevention (CDC) (24,27), based on Advisory Committee on Immunization Practices (ACIP) principles (37), but would additionally suggest deprioritizing individuals with csCOVID-19 for a predefined period of time [currently 90 days (27)] or until enough vaccines are available (see Conclusion section below for further detail).

We suggest identifying specific products (vaccines), whose efficacy parameters and administration specifics (number of doses and separation interval), as well as their projected speed of manufacturing and country-specific allocation in time can be determined.

We then propose using all of the parameters derived from points 1 and 2 to model predictions for attainment of CDC/ACIP prespecified goals, thus informing modifications needed to improve the performance of vaccine allocations periodically.

Importantly, we suggest that the above models account also for scenarios, in which individuals with prior csCOVID-19 would have their vaccination postponed, to maximize immunization of all susceptible individuals with the goal of the most time- and cost-effective attainment of population-wide herd immunity (2) based on incremental vaccine availability (this should account for growth based on effective reproduction number of COVID-19 [R_t] at the time).

Finally, in each modeling iteration, we suggest incorporating projected rates of vaccine refusal in the immediately anticipated vaccination groups based on CDC/ACIP prioritization scheme, as these are currently not insignificant and are likely to influence the attainment of herd immunity as well as R_t (16,36).

Similar modeling with a modified list of parameters has recently been undertaken by a multi-institutional group of investigators (6). Their modeling shows positive impact on reductions in infections, deaths, and years of life lost when prior seropositivity is accounted for in vaccination strategies.

Conclusion

In our mind, the only real issue with operationalization of this vaccination delay in individuals with a history of csCOVID-19 is the lack of clear understanding regarding the correlate of immune protection, although a hint regarding antibody titers needed to protect from current SARS-CoV-2 variants are starting to emerge from in vitro neutralization assays with postvaccination sera (32). Therefore, the anticipated problems could be: 1. How to determine who is protected; and 2. What to do about those whose protection is presumed but their risk level for severe outcomes is high.

Given that reinfection after csCOVID-19 seems rare, anyone who is within the CDC-specified period of time (27) from meeting the definition of a csCOVID-19 convalescent, and does not otherwise belong to a high-risk group (e.g., by age or immune status), should be protected and could delay the vaccination until the end of the CDC-specified period, or until there is enough vaccine available to vaccinate all susceptible individuals, who do not meet the above definition (whichever is shorter, with respect to other prioritization criteria, i.e., a first responder would be reprioritized once s/he is no longer considered protected)

The decision on the priority for these individuals should be periodically re-evaluated based on the contemporary evidence regarding their specific risk of severe outcome and likelihood of exposure, and informed based on vaccine availability.

Considering convalescents along with the immunized is also an important equity issue, and any relaxation of epidemiological measures for both of these groups together may provide further incentive to accept vaccination by showing how much closer we may already be to herd immunity protecting the vulnerable. Recognition, not further epidemiological punishment is likely to get us to herd immunity faster and thus enable further relaxation of economically and psychologically harmful restrictions.

Lastly, even after some reasonable deprioritization of vaccination for convalescents, further doses can be saved by using one dose boosting, as this has been shown highly effective in at least three separate experiments, showing the second dose at the usual dosing interval to be unnecessary, and even somewhat increasing the risk of postvaccination adverse events (25,29,47). Such single-dose boosting could, and perhaps should be considered in COVID-19 convalescents who are at an increased risk by virtue of their occupation, for example, health care workers and first responders. The speed of vaccination is all the more important now, after we have learned that the more time the virus has, the more escape mutations are likely to challenge effective immunity (33).

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this work.

References

Abu-Raddad

, Chemaitelly

, Coyle

, et al. SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35weeks. medRxiv, DOI: 10.1101/2021.01.15.21249731.

Anderson

, Vegvari

, Truscott

, et al. Challenges in creating herd immunity to SARS-CoV-2 infection by mass vaccination. Lancet, 2020; 396:1614–1616.

Bastard

, Rosen

, Zhang

, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science, 2020; 370:eabd4585.

Beauchamp

, and Childress

JF.

Principles of Biomedical Ethics, 5th ed. Oxford University Press, NK, 2001, pp. 454.

BNO News: COVID-19 reinfection tracker. Available at: https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker/ accessed January 10, 2020 .

Bubar

, Reinholt

, Kissler

, et al. Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science, 2021; 371:916–921.

Burki

The online anti-vaccine movement in the age of COVID-19. Lancet Digit Health, 2020; 2:e504–e505.

Cervia

, Nilsson

, Zurbuchen

, et al. Systemic and mucosal antibody responses specific to SARS-CoV-2 during mild versus severe COVID-19. J Allergy Clin Immunol 2020 [Epub ahead of print], DOI: 10.1016/j.jaci.2020.10.040.

Chandrashekar

, Liu

, Martinot

, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science, 2020; 369:812–817.

10.

Corbett

, Flynn

, Foulds

, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med, 2020; 383:1544–1555.

11.

Coronavirus Vaccine Update With Paul Offit. AMA Education Hub via JAMA Network, December 4, 2020. Available at: https://edhub.ama-assn.org/jn-learning/video-player/18565560?widget=personalizedcontent&previousarticle=18565646 accessed December 6, 2020 .

12.

COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Available at: https://coronavirus.jhu.edu/map.html accessed December 4, 2020 .

13.

Dan

, Mateus

, Kato

, et al. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection. bioRxiv, DOI: 10.1101/2020.11.15.383323.

14.

Deng

, Bao

, Liu

, et al. Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Science, 2020; 369:818–823.

15.

Dooling

, McClung

, Chamberland

, et al. The advisory committee on immunization practices' interim recommendation for allocating initial supplies of COVID-19 vaccine—United States, 2020. MMWR Morb Mortal Wkly Rep 2020, DOI: 10.15585/mmwr.mm6949e1externalicon.

16.

Funk

, and Tyson

. Intent to Get a COVID-19 Vaccine Rises to 60% as Confidence in Research and Development Process Increases. December 3, 2020. Available at: https://www.pewresearch.org/science/2020/12/03/intent-to-get-a-covid-19-vaccine-rises-to-60-as-confidence-in-research-and-development-process-increases/ accessed December 10, 2020 .

17.

Gandhi

, Beyrer

, and Goosby

. Masks do more than protect others during COVID-19: reducing the inoculum of SARS-CoV-2 to protect the wearer. J Gen Intern Med, 2020; 35:3063–3066.

18.

Goldman

, Wang

, Roltgen

, et al. Reinfection with SARS-CoV-2 and Failure of Humoral Immunity: a case report. medRxiv [Preprint] 2020, DOI: 10.1101/2020.09.22.20192443.

19.

Grifoni

, Weiskopf

, Ramirez

, et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell, 2020; 181:1489.e15–1501.e15.

20.

Gupta

, Bhoyar

, Jain

, et al. Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS-CoV-2. Clin Infect Dis 2020:ciaa1451 [Epub ahead of print], DOI: 10.1093/cid/ciaa1451.

21.

Hall

, Foulkes

, Charlett

, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet, 2021; 397:1459–1469.

22.

Hansen

, Michlmayr

, Gubbels

, et al. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet 2021 [Epub ahead of print], DOI: 10.1016/S0140-6736(21)00575-4.

23.

Harvey

, Rassen

, Kabelac

, et al. Association of SARS-CoV-2 seropositive antibody test with risk of future infection. JAMA Intern Med, 2021:e210366. doi: 10.1001/jamainternmed.2021.0366.

24.

How CDC Is Making COVID-19 Vaccine Recommendations. December 3, 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations-process.html#groups-considered accessed December 9, 2020 .

25.

Hunter

, and Brainard

Estimating the effectiveness of the Pfizer COVID-19 BNT162b2 vaccine after a single dose. A reanalysis of a study of ‘real-world’ vaccination outcomes from Israel. medRxiv, DOI: https:/doi.org/10.1101/2021.02.01.21250957.

26.

IDSA—COVID-19 Real-Time Learning Network: Vaccines

FAQ.

2020. Available at: https://www.idsociety.org/covid-19-real-time-learning-network/vaccines/vaccines-information—faq/ accessed January 10, 2021 .

27.

Interim Considerations for COVID-19 Vaccination of Healthcare Personnel and Long-Term Care Facility Residents. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19/clinical-considerations.html accessed December 6, 2020 .

28.

Iwasaki

What reinfections mean for COVID-19. Lancet Infect Dis 2020 [Epub ahead of print], DOI: 10.1016/S1473-3099(20)30783-0. Erratum in: Lancet Infect Dis 2020.

29.

Krammer

, Srivastava

, and Simon

Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. medRxiv, DOI: 10.1101/2021.01.29.21250653.

30.

Larson

, Brodniak

, Voegtly

, et al. A case of early re-infection with SARS-CoV-2. Clin Infect Dis 2020:ciaa1436 [Epub ahead of print], DOI: 10.1093/cid/ciaa1436.

31.

Le Bert

, Clapham

, Tan

, et al. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J Exp Med, 2021; 218:e20202617.

32.

Liu

, Liu

, Xia

, et al. Neutralizing Activity of BNT162b2-Elicited Serum. N Engl J Med 2021 [Epub ahead of print], DOI: 10.1056/NEJMc2102017.

33.

Liu

, Van Blargan

, Bloyet

, et al. Identification of SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. Cell Host Microbe 2021 [Epub ahead of print], DOI: 10.1016/j.chom.2021.01.014.

34.

Lumley

, O'Donnell

, Stoesser

, et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N Engl J Med 2020:NEJMoa2034545 [Epub ahead of print], DOI: 10.1056/NEJMoa2034545.

35.

Luo

, Liu

, Liao

, et al. Contact settings and risk for transmission in 3410 close contacts of patients with COVID-19 in Guangzhou, China: a prospective cohort study. Ann Intern Med, 2020; 173:879–887.

36.

Many remain doubtful about getting COVID-19 vaccine. 2020. Available at: https://apnorc.org/projects/many-remain-doubtful-about-getting-covid-19-vaccine/ accessed December 10, 2020 .

37.

McClung

, Chamberland

, Kinlaw

, et al. The advisory committee on immunization practices' ethical principles for allocating initial supplies of COVID-19 vaccine—United States, 2020. MMWR Morb Mortal Wkly Rep, 2020; 69:1782–1786.

38.

Moderna Announces Primary Efficacy Analysis in Phase 3 COVE Study for Its COVID-19 Vaccine Candidate and Filing Today with U.S. FDA for Emergency Use Authorization. 2020. Available at: https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-primary-efficacy-analysis-phase-3-cove-study accessed December 6, 2020 .

39.

Mulder

, van der Vegt

DSJM

, Oude Munnink

, et al. Reinfection of SARS-CoV-2 in an immunocompromised patient: a case report. Clin Infect Dis 2020:ciaa1538 [Epub ahead of print]. DOI: 10.1093/cid/ciaa1538.

40.

National Academies of Sciences, Engineering, and Medicine. Framework for Equitable Allocation of COVID-19 Vaccine. Washington, DC: The National Academies Press, 2020.

41.

Petersen

, Kristiansen

, Hanusson

, et al. Long COVID in the Faroe Islands—a longitudinal study among non-hospitalized patients. Clin Infect Dis 2020:ciaa1792 [Epub ahead of print], DOI: 10.1093/cid/ciaa1792.

42.

Petito

, Falcinelli

, Paliani

, et al. Neutrophil more than platelet activation associates with thrombotic complications in COVID-19 patients. J Infect Dis 2020:jiaa756 [Epub ahead of print], DOI: 10.1093/infdis/jiaa756.

43.

Pfizer and BioNTech conclude phase 3 study of COVID-19 vaccine candidate, meeting all primary efficacy endpoints. 2020. Available at: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine accessed December 4, 2020 .

44.

Prado-Vivar

, Becerra-Wong

, Guadalupe

, et al. A case of SARS-CoV-2 reinfection in Ecuador. Lancet Infect Dis 2020 [Epub ahead of print], DOI: 10.1016/S1473-3099(20)30910-5.

45.

Rodda

, Netland

, Shehata

, et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell 2020 [Epub ahead of print], DOI: 10.1016/j.cell.2020.11.029.

46.

Rydyznski Moderbacher

, Ramirez

, Dan

, et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell, 2020; 183:996.e19–1012.e19.

47.

Saadat

, Tehrani

, Logue

, et al. Binding and neutralization antibody titers after a single vaccine dose in health care workers previously infected with SARS-CoV-2. JAMA 2021:e213341 [Epub ahead of print], DOI: 10.1001/jama.2021.3341.

48.

Simmonds

, Williams

, and Harvala

Understanding the outcomes of COVID-19—does the current model of an acute respiratory infection really fit? J Gen Virol 2020 [Epub ahead of print], DOI: 10.1099/jgv.0.001545.

49.

, and Woo

. Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis. BMJ, 2020; 371:m4750.

50.

Sollini

, Ciccarelli

, Cecconi

, et al. Vasculitis changes in COVID-19 survivors with persistent symptoms: an [¹⁸F]FDG-PET/CT study. Eur J Nucl Med Mol Imaging, 2020:1–7 [Epub ahead of print], DOI: 10.1007/s00259-020-05084-3.

51.

Tarke

, Sidney

, Methot

, et al. Negligible impact of SARS-CoV-2 variants on CD4 ⁺ and CD8 ⁺ T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv [Preprint] 2021, DOI: 10.1101/2021.02.27.433180.

52.

Tillett

, Sevinsky

, Hartley

, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis 2020 [Epub ahead of print], DOI: 10.1016/S1473-3099(20)30764-7.

53.

, Hung

, Ip

, et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020:ciaa1275 [Epub ahead of print], DOI: 10.1093/cid/ciaa1275.

54.

, Goh

, Tan

, et al. Cerebral venous thrombosis in patients with COVID-19 infection: a case series and systematic review. J Stroke Cerebrovasc Dis, 2020; 29:105379.

55.

van Doremalen

, Lambe

, Spencer

, et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature, 2020; 586:578–582.

56.

Van Elslande

, Vermeersch

, Vandervoort

, et al. Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain. Clin Infect Dis 2020:ciaa1330 [Epub ahead of print]. DOI: 10.1093/cid/ciaa1330.

57.

Voysey

, Costa Clemens

, Madhi

, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. Lancet 2020. DOI: 10.1016/S0140-6736(20)32661-1.

58.

Wegwarth

, Wagner

, Spies

, et al. Assessment of German public attitudes toward health communications with varying degrees of scientific uncertainty regarding COVID-19. JAMA Netw Open, 2020; 3:e2032335.

59.

Woodruff

, Ramonell

, Nguyen

, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol, 2020; 21:1506–1516.

60.

, Tostanoski

, Peter

, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science, 2020; 369:806–811.

61.

Zhang

, Bastard

, Liu

, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, 2020; 370:eabd4570.