COVID-19 Vaccine-Acquired vs. Disease-Acquired Immunity: Which is Better?
The gist: Many seem to hold to the incorrect idea that immunity acquired through infection is superior to immunity acquired by vaccination but multiple examples show this isn’t true: recovery from tetanus generally does not confer any protection while vaccination induces protection in virtually everyone, vaccination is far more protective against HPV than infection, and some infectious diseases can recur or develop into chronic diseases like varicella (chickenpox) and hepatitis B. COVID-19 is among the most dangerous respiratory infections that any of us will ever face in our lives. It has killed at least 4 million people in the course of this pandemic (and this is almost certainly an undercount), many of whom were previously healthy, and it has also left uncountably many more struggling with prolonged disability that remains poorly understood and with very limited options as far as treatment. By comparison, any serious adverse events following vaccination are extremely rare- on the order of 1 to 10 per 1,000,000 doses of vaccine, and effectiveness across all variants to date has been largely preserved. Furthermore, mRNA vaccines against COVID-19 show much higher levels of neutralizing antibodies with better ability to cross-protect against variants than recovery from COVID-19, and comparable T cell responses. The durability of these vaccines furthermore looks to be robust. Data are more limited for other vaccine types (though recent data on the Johnson & Johnson/Janssen vaccine confirms excellent durability), but the fundamental point is that the proposition that we get to herd immunity through infection is utterly immoral and furthermore ignorant of history. If this were possible to do, measles would have accomplished it because it spreads very rapidly through the population and generates robust protective immunity in virtually everyone who survives it, but we saw regularly huge outbreaks every 2-5 years. That’s because of population turnover: eventually enough people who were immune died and enough people who weren’t were born, allowing for steady, regular outbreaks. Continuously allowing SARS-CoV-2 to infect people will also create new opportunities for the virus to evolve, potentially escaping pre-existing immunity altogether as the endemic common cold coronaviruses do; recent data shows that the delta variant appears to have a heightened risk of both reinfections and also infection post-vaccination. Though most people do seem to generate robust immune memory after recovery from COVID-19, there is no simple way to assess whether or not individual recovered patients have achieved this, and while reinfection is rare and usually milder when it does occur, this is not always the case with some reinfections being more severe and even fatal. Available evidence indicates that the quality of immunity against SARS-CoV-2 is drastically enhanced by vaccination with even a single dose of vaccine after recovery, and while side effects are more intense in recovered patients who are vaccinated, vaccination of recovered patients appears safe. Therefore, after recovery (or after a period of 90 days if convalescent plasma or monoclonal antibodies were received), even recovered patients should be vaccinated against COVID-19.
Yewdell, J. W. (2021). Individuals cannot rely on COVID-19 herd immunity: Durable immunity to viral disease is limited to viruses with obligate viremic spread. PLoS Pathogens, 17(4), e1009509.
Background
Kaufmann, S. H. E., Rouse, B. T. & Sacks, D. L. The immune response to infection. (American Society for Microbiology, 2010).
As the pandemic has progressed, so has our understanding of the immunity we develop against SARS-CoV-2. It does appear that most (but not all) cases of COVID-19 do result in a robust immune response and the generation of immunological memory (though this has many important caveats and has regrettably been weaponized as an instrument of politics rather than public health). I think some have engaged in revisionist history though in claiming that there was no other possible outcome; this is certainly great news, but this was in no way a guarantee. For one thing, in general the viruses that result in long-lived immunological memory are those that disseminate either through the blood or lymphatic system, but viremia is a rare phenomenon in COVID-19 and predicts severe disease (which is, as a proportion of infections, also rare). Note however that even though mild disease is so named, this does not necessarily mean a mild or self-limiting illness; mild disease can be extremely taxing but is mostly distinguished on the basis of not involving the lower respiratory tract or causing significant decline in oxygen saturation or requiring hospitalization. Additionally, common cold coronaviruses (CCCs) regularly reinfect people through antigenic drift (mutations in the proteins of the virus to escape antibodies) in as few as 6 months. This builds on prior work demonstrating that in human challenge studies, reinfection with the same CCC one year after initial encounter, reinfection can still occur though at reduced severity. We also see that for other respiratory viruses, durable immunological protection is not a certainty, e.g. RSV seems to be able to cause reinfection with antigenically similar isolates a significant proportion of the time for example (each challenge resulted in reinfection at least one-fourth of volunteers, with initially about half of these being symptomatic and progressively decreasing with subsequent challenges), and even though influenza A is classically regarded as producing long-lived immunity against similar strains, in a human challenge study, symptomatic reinfection occurred with most of the volunteers. Immunity to respiratory viruses generally is reviewed here. Concerns were further amplified when a study showed that in patients who died of COVID-19, germinal centers in the lymph nodes (a structure known to be important for the development of long-lasting humoral immunity) were atrophied (though of course this analysis does not tell us whether the outcome was a cause or effect of death from COVID-19 or whether it generalized to other milder cases; interesting a preprint has demonstrated that, in mice, despite absence of the TFH cells critical for the formation of germinal centers, high levels of potent, neutralizing antibodies do develop, though class switching is inhibited). In a broad sense, durable immunity against mucosal pathogens (like those that infect the respiratory tract) is a challenge as demonstrated by vaccination, because the default response at barrier tissues like the respiratory tract on exposure to antigen is tolerance, generally mediated by regulatory T cells.
It is also worthwhile to remind people that in terms of the quality of immunity generated by vaccination, as compared with infection, it is not a given that vaccination will elicit inferior protection (setting aside the dangers of the infection).
The Immune Response against SARS-CoV-2
Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021).
Hartenian, E. et al. The molecular virology of coronaviruses. J. Biol. Chem. 295, 12910–12934 (2020).
SARS-CoV-2 is a positive-sense, unsegmented RNA virus in the Betacoronavirus genus which principally initiates infection of susceptible hosts through inhalation of infectious particles contained within respiratory droplets and aerosols (though primarily through close-range, prolonged contact with infected hosts), wherein it enters permissive and susceptible cells, principally through the ACE2 receptor. The early mucosal immune response to SARS-CoV-2 is reviewed here, though details on its specific interactions are not very well understood; recent data suggest epithelial cells in the nasopharynx have blunted antiviral responses and enhanced type II interferon production in severe disease. SARS-CoV-2 encodes within it a suite of proteins that are very effective for evading innate immune mechanisms of protection such as type 1 and type III interferons. The timing of the interferon response appears to be critical, as it appears that late production of interferon contributes to immunopathology, whereas early, rapid response is able to control viral replication. Indeed, COVID-19 is associated with a massive type 1 interferon response. One concern that has been raised with COVID-19 is that infection of the upper respiratory tract may facilitate neuroinvasion of the virus, which has been demonstrated on autopsies and in mouse models (though neuroinvasion in mouse models is a common feature of many coronavirus infections and thus the significance of this is not immediately clear, and autopsy findings are hard to extrapolate to the more common milder cases); however recent imaging studies show loss of greymatter in regions corresponding to neurological symptoms in COVID-19. The duration of neurological deficits in COVID-19 is not currently known, but this appears to be a more common phenomenon than for many viral infections and a substantial contributor to disease severity. COVID-19 also seemingly provokes a hypercoagulable state which can result in inappropriate clot formation, seemingly through immunothrombotic mechanisms discussed here and here. Another concern that has been raised with COVID-19 is the potential for the development of diabetes mellitus; autopsy samples of COVID-19 decedents are able to identify virus within the beta cells of the pancreas wherein it appears to cause transdifferentiation. In human pancreas cell culture models, SARS-CoV-2 is able to productively infect both the endocrine and exocrine pancreas. Glycometabolic control among some recovered patients appears to be impaired a significant proportion of the time for a period of at least 2 months. Furthermore, SARS-CoV-2 antibody responses seem to involve Tbet+ B cells as a source of neutralizing antibodies, which are generally associated with systemic lupus erythematosus where they are thought to be pathogenic; the extent of these B cell responses correlates with disease severity. In exoproteome profiling of patients with SARS-CoV-2 infection, diverse functional autoantibodies against tissue antigens and cytokines are elicited and in mice are able to worsen disease; it is possible that these autoantibodies may play a role in the post-acute consequences of COVID-19, which are manifold (see Box 1). The duration of these symptoms is variable but in one recent prospective study approximately one-fifth of patients were struggling with persistent symptoms after 12-months, with females being higher risk than males, though the overall cohort was small. Viral infection is a well-characterized trigger of autoimmune disease, and thus there is concern that SARS-CoV-2 may also do the same. SARS-CoV-2 is known to cause multisystem inflammatory syndrome (in children and more rarely in adults), a hyperinflammatory disease that remains poorly understood and is associated with substantial morbidity and occasionally mortality; recent data implicate a retained viral reservoir in the intestine which results in a loss of mucosal barrier integrity, endotoxemia, and viral antigenemia on top of a superantigen response. A CDC analysis of COVID-19 from January to May 2020 covering 1.5 million patients found that 14% were hospitalized and 5% died. Analysis of infection fatality rate shows a strong age gradient with values ranging from 0.002% for those aged 10 to 15% for those aged 85 or older. However, these data do not take into account novel variants, which some data suggest are associated with a higher risk of fatality. Overall it can be said that while most cases of COVID-19 are mild, in that they do not require hospitalization, the potential for deleterious outcomes is vast, ranging from post-acute consequences of infection in previously healthy people which can be literally disabling, to even death. While it is tempting and psychologically mollifying to presume that SARS-CoV-2’s virulence will attenuate over time, it is important to bear in mind that the primary selection pressure is in favor of enhanced transmissibility rather than lethality, and viruses can and have evolved heightened lethality if it was associated with a fitness advantage in the past.
The immune response to SARS-CoV-2 infection, as compared with vaccination, is broader in scope. SARS-CoV-2’s genome encodes approximately 30 proteins within it (see table 1), while most vaccines available contain just the spike protein (the exception being inactivated vaccines like the CoronaVac and BBIBP-CorV vaccines which use whole, inactivated virus), which results in exposure to many more epitopes from infection. The exact significance of this as far as protection is not entirely clear presently because a correlate of protection for SARS-CoV-2 is not yet defined, though presumably having more T cell epitopes which can be targeted makes evolving immune escape more improbable compared with having fewer epitopes; in studies of patient outcomes, robust T cell immunity is critical for recovery and sex disparities in patient outcomes may be related to differences in the T cell response between sexes throughout the lifespan (this may be related to sex differences in kynurenic acid metabolism). Nonetheless, for most vaccine-preventable diseases, antibodies are the principal correlate of protection, and it has been shown that in macaques, passive transfer of antibodies against the spike protein is sufficient to prevent the development of COVID-19, even at relatively low titers, and the earlier neutralizing antibodies appear in those with acute COVID-19, the better patients fare. Furthermore, multiple studies have demonstrated that antibodies directed against non-structural and accessory proteins of SARS-CoV-2 (which are excluded from most vaccines) correlates with worse outcomes. It is thought that prior coronavirus infections can bias towards the development of non-neutralizing antibodies in infection that associates with more severe disease, and this is more likely to occur in elderly patients who may be more experienced with prior coronavirus infection; this same study demonstrates that, in animals, antibodies against ORF8 and nucleocapsid protein are not protective against the development of COVID-19. Furthermore outpatients showed a higher ratio of anti-N to anti-S antibodies compared with hospitalized patients. Additionally, afucosylated antibodies in severe COVID-19 are thought to contribute to the hyperinflammatory state, these antibodies tending to target proteins on the viral surface such as spike protein, which may be related to the age of patients as these post-translational modifications decrease with age. Severe COVID-19 also tends to produce much higher antibody titers. There is notably a decrease in neutralizing antibody titer (though largely preserved Fc effector functions) among the those who recovered from mild COVID-19 over time, as well as a general trend towards decreasing antibody titers among most patients who recover; however this should not be used to infer a loss of protection, and indeed some data indicate an increase in the neutralization capacity of antisera against variants over time in spite of reduced absolute titer. At the respiratory mucosa, there also appears to be robust induction of secretory IgA, which has extremely potent neutralizing activity, and this persists well past the decline of antibodies in the sera. Antibodies continue to evolve over time in a manner that suggests persistence of viral antigens within the body.
A recent study has demonstrated that among patients who generally had mild cases of COVID-19, long-lived IgG-secreting plasma cells against spike protein were present in the bone marrows of 15 of 19 of them, suggesting durable humoral immunity, as well as circulating memory B cells; however what is commonly excluded from this very popular soundbite is that that also means that these markers of humoral immunity were absent among 4 of the 19 patients- about one-sixth of them. Interestingly, in the SIREN study of reinfections, over the seven-month observation period, there was an 84% reduced risk of confirmed reinfection which agrees very well with these results. A large analysis of PCR results in Denmark following 4 million people from March to December 2020 demonstrated that the risk of reinfection was reduced by about 80% in most individuals, but in those over 65 it was just 47.1%; however these are PCR data only and thus do not tell us about the clinical severity of COVID-19 in these patients (though presumably most of these PCRs do reflect patients who sought testing after developing symptoms). Still, the results deserve attention given how serious COVID-19 can be for the elderly and underscore the need for additional protection measures like vaccination even following recovery. Another study builds on the evidence that recovery from SARS-CoV-2 does generally seem to confer durable immunity by profiling patients’ antibody and T cell responses noting that responses are preserved for at least 8 months, which is encouraging (though notably the study assessed primarily those who had mild disease). Similar findings have been noted by other groups. Still though, it is important to keep in mind that in the latter study approximately 10% of patients did not have immunological memory across the 3 assessed compartments, and on a large population scale that could potentially result in significant disease and public health burden upon challenge with SARS-CoV-2. Real-world data on the immunological protection conferred by COVID-19 are subject to the key limitations of being of relatively short-duration (on the timescale of immunity) and with most studies having occurred before the emergence of novel variants of concern. While we do have data that suggests that T cell responses across variants are essentially invariant, it is hard to define the extent to which this is protective clinically, though it is likely that most recovered patients are protected from severe disease. The most recent data from Public Health England do show that the delta variant is associated with a heightened risk of reinfection among those whose primary infections occurred greater than 180 days prior.
Can we get to herd immunity against COVID-19 by infection? Insight from measles
Nelson, K. E. & Williams, C. Infectious disease epidemiology. (Jones and Bartlett, 2013).
It is tempting to wonder whether it might be feasible to attain herd immunity from infection alone, and indeed some have vociferously argued that we in fact should attempt this. Firstly, it’s important to define herd immunity here, as that term has gotten to be quite confusing. Herd immunity refers to a state where, within some population, a critical proportion of individuals have immunity against an infectious disease such that it cannot effectively spread throughout the population. When there are no endemic cases of a given infectious disease in some region, it is said to be eliminated from the region. When the only specimens of the pathogen in question exist in labs, and it does not circulate anywhere in the world, it is said to be eradicated (only two infectious diseases have been eradicated: smallpox and rinderpest- both via aggressive vaccination campaigns). If no specimens of the pathogen exist anywhere, the disease is considered extinct (no examples currently). Because of the wide range in hosts, SARS-CoV-2 is unlikely to ever be eradicated (though if a universal coronavirus vaccine ever emerges, that might change), but elimination is likely possible.
Khoury, D. S. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 27, 1205–1211 (2021).
Measles is another respiratory virus of great public health importance that can help offer some insights into the situation we would be in if we attempted to reach herd immunity entirely through infection- a situation that is categorically unacceptable and would not work. Measles is transmitted in an airborne manner with a secondary attack rate greater than 90%, and aerosols can retain infectivity for hours; R0 for measles is commonly stated as being 12-18 but there are outbreaks where it has been measured to be over 700. However, in spite of its extraordinary contagiousness, measles generates extremely durable (generally lifelong) immunity in virtually all who survive it and though there are 24 genotypes recognized, the virus has a single serotype and is extremely unlikely to evolve to escape antibodies (note however that with SARS-CoV-2, novel variants demonstrate varying degrees of antibody evasion and each infection is an opportunity for variants to emerge which are more resistant to prior immunity and more transmissible, potentially becoming more virulent as a byproduct of those changes). These qualities would suggest that it is ideally suited for attaining herd immunity by infection: the virus could rapidly infect entire populations and induce lifelong immunity in virtually all survivors (though for the record the public health toll from measles is astonishingly great; measles also has the ability to erase previously-held immunological memory, thereby increasing all-cause mortality for years after infection). But we know it didn’t. Figure 16-4 shows epidemic cycles of measles in England and Wales from 1950 to 1979. There are massive outbreaks every 2-5 years, until the vaccine is introduced in 1968, after which cases begin to decline substantially and the inter-epidemic period gets longer. Why? Eventually the proportion of your population that is immune to measles dies, and eventually people with no immunity to measles are born. This results in a new niche for the virus to infect, causing outbreaks. Vaccination has successfully eliminated measles from much of the world and measles is thought to be a good candidate for eradication as humans are required for its sustained transmission.
Vaccine-acquired immunity
Most immunologic data regarding vaccine acquired immunity focuses on mRNA vaccines. For the mRNA vaccines, neutralizing antibody titers appear to be higher than those of most convalescent patients, and they correlate with the extent of protection against COVID-19 per Khoury et al; the neutralization capacity of antibodies in sera of vaccinees also appears to be better in FRNT assays. It is furthermore observed that mRNA vaccines elicited antibodies are more resistant to changes in the SARS-CoV-2 spike protein, and can seemingly cause recall responses from prior coronavirus infections to target conserved regions of the spike protein. This may be related to the pre-fusion stabilization of the spike protein encoded by the mRNA vaccines (which would not occur with SARS-CoV-2 because this impairs the ability of the spike protein to enable fusion and cell entry and therefore be selected against), but the reasons are not understood. Furthermore, aspirates of the proximal lymph nodes of vaccinees demonstrate persistent germinal center responses suggestive of long-lived plasma cell production and durable memory B cells, indicating robust humoral immunity. At the nasopharynx, lavages have demonstrated that vaccinees have higher levels of antibodies than recovered patients, though data are limited on this point and mucosal immunity of vaccinees in the broad sense is not currently well characterized. The mechanism by which IgG may arise within the upper respiratory tract is incompletely understood; one thought is that it is actively transported in via FcRN in the lungs and then enters the upper airway through the mucociliary escalator. Recent data also further demonstrates continued affinity maturation of the B cells in recipients of mRNA vaccines. Profiling of the T cell responses in patients who received a quarter dose of the Moderna vaccine revealed responses similar in quality and magnitude to those who had recovered from COVID-19, and the responses across variants are similarly well conserved as the spike protein contains many T cell epitopes. Data also show mRNA vaccine T cell responses are similar across all variants. Furthermore, at the public health level, it has been demonstrated explicitly that higher levels of vaccination are associated with reduced SARS-CoV-2 genomic diversity across a population, and in comparing infections post-vaccination cases to primary infections, patients tend to have a reduced viral load and are infectious for shorter periods of time. Taken together, the available data suggest that mRNA vaccines produce an immune response that results in superior humoral immunity than infection and comparable T cell responses; more data are needed to assess how mucosal immunity compares with that from infection.
Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).
Questions remain about the extent to which protection from the vaccines is durable and how well it compares clinically over sufficiently long periods of time to reliably render conclusions, though there are several clinical studies of vaccine effectiveness in the real world (again focusing on mRNA vaccines). The half-life for Moderna vaccinees’ antibodies 6 months after vaccination was estimated to be 202 days for live virus neutralization, however, which is encouraging. An evaluation of high-risk patients measured an effectiveness of 96.2% for the Pfizer and 98.2% for the Moderna vaccines, though this preceded the emergence of some variants of concern. A single dose of mRNA vaccine offered substantial protection (80 and 85% respectively) against hospitalization and death from COVID-19 among older adults. Among adults over the age of 65, mRNA vaccines were found to be 94% effective against the risk of hospitalization following 2 doses. Another study found 90% effectiveness against infection of any severity with the mRNA vaccine series. One study of patients in Qatar found a slightly reduced risk of a positive PCR among recent vaccinees compared with those who had recovered from COVID-19, though the difference was not statistically significant. Data also show that the Pfizer/BioNTech vaccine retains effectiveness against the alpha and beta variants, the Moderna vaccine retains effectiveness against the beta variant, and the effectiveness of completed vaccine series against the Delta variant is largely preserved as well (provided both doses are given). Data regarding whether or not SARS-CoV-2 vaccines can prevent infection are discussed in this post. There is significant evidence demonstrating that COVID-19 vaccines reduce transmission of COVID-19. Real-world comparisons of vaccines vs. prior infection are limited as far as their protective efficacy, largely focusing on relatively short durations of time.
A salient point for vaccination is not only the attainment of herd immunity as described above, but fundamentally vaccination represents a far safer path to protection than does infection. While true that it is not without risk, serious adverse events following vaccination are exceptionally rare, although the mRNA vaccines in particular have significant reactogenicity. Anaphylaxis is measured to occur on the order of 1 to 10 per 1,000,000 doses of vaccine. The Johnson & Johnson/Janssen vaccine has been very rarely associated with thrombosis with thrombocytopenia syndrome which most recent numbers estimate a risk of approximately 3 per 1 million doses. Similarly, Guillain-Barre syndrome has been observed very rarely at a frequency of approximately 7.8 cases per million doses following both the Johnson & Johnson/Janssen vaccine and the Oxford/Astra-Zeneca vaccine (approximately 4.4 cases per million doses), though this has also been noted with COVID-19 (but the frequency is not yet well-defined). Among younger individuals and predominantly males, the mRNA vaccines have been associated with myocarditis with rates reported as high as 1 per 3000 cases in Israel among males 16 to 24, though numbers elsewhere are much lower; still, SARS-CoV-2 has been associated with myocarditis as frequently as 2.3% of cases in college athletes. It is untenable to argue that vaccination represents a greater danger to one’s health than does COVID-19. Furthermore, vaccines may be rapidly updated to account for the emergence of novel variants escaping immunity or waning protection (though there is presently no indication that this is needed for most people), whereas willfully contracting COVID-19 again to protect against it largely obviates the point of that protection.
Crotty, S. Hybrid immunity. Science 372, 1392–1393 (2021).
Vaccination post-COVID-19
Vaccination post-COVID-19 is recommended upon resolution of disease/conclusion of isolation, or following 90 days after the use of either monoclonal antibodies or convalescent plasma in the US. Some countries recommend a single dose of vaccine for recovered patients based on available immunologic data (detailed shortly) which do not indicate a benefit for a second dose; others however are more conservative and recommend both doses for vaccines with a 2-dose series as this is known to have superior protection than single doses as per clinical trials and questions linger about the durability of protection from a single dose of vaccine for COVID-19. Upon vaccination of recovered patients, there is a massive increase in the neutralizing antibody responses in significant excess of that of patients who have not had SARS-CoV-2 infections; these antibodies are furthermore more effective at cross-neutralization of variants of concern, and even significantly enhancing the ability to neutralize SARS-CoV-1’s spike protein. There is additionally a substantial boost to the T cell response. While certainly the vaccines are more reactogenic in those who have recovered from COVID-19 than those who have never had it, available evidence does not indicate a safety problem. Though reinfection is rare, it can happen, and it can even be fatal, and vaccination represents a reliable means by which to protect against those consequences. Hansen et al did note that just 47.1% of those over the age of 65 were protected from reinfection over a 3-6 month period of follow up, suggesting that vaccination following recovery may not only be beneficial but in fact critical in some patients. At the bedside, the key point is that there is no simple way to assess for any individual patient whether or not they have protection against COVID-19 following recovery, though it is probable that most will (for example, a study recently showed that cases post-vaccination with variants had similar antibody titers to patients who proved protected against COVID-19 on a fishing boat vessel). Therefore, vaccination of even recovered patients makes sense for their safety and at the public health level.
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