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Correlates of protection against SARS‐CoV‐2 infection and COVID‐19 disease

Abstract Antibodies against epitopes in S1 give the most accurate CoP against infection by the SARS‐CoV‐2 coronavirus. Measurement of those antibodies by neutralization or binding assays both have predictive value, with binding antibody titers giving the highest statistical correlation. However, the protective functions of antibodies are multiple. Antibodies with multiple functions other than neutralization influence efficacy. The role of cellular responses can be discerned with respect to CD4+ T cells and their augmentation of antibodies, and with respect to CD8+ cells with regard to control of viral replication, particularly in the presence of insufficient antibody. More information is needed on mucosal responses.

principles are that protection against infection is different from protection against disease, that more than one immune factor may correlate with protection, and that protection against mucosal infection may depend on different factors than protection against systemic disease. Moreover, memory may be a mechanism of protection if it results in rapid induction of immune functions after exposure, which in the case of COVID-19 memory must likely act within the first week of infection to contribute to protection.
The need for rapid protection of populations against  has evoked the use of multiple vaccine platforms. However, thus far the common feature of those platforms is that protection correlates with the induction of neutralizing antibodies. Although evidence for the primacy of those antibodies for protection will be presented below, we will also summarize the evidence that memory B cells,

| HUMOR AL IMMUNIT Y/NEUTR ALIZING ANTIBOD IE S
SARS-CoV-2 is a single-stranded positive-sense RNA virus of approximately 29.9kb and its genome codes for four structural proteins and sixteen non-structural proteins (nsp1−16). The structural nucleocapsid protein (N) forms the capsid outside the genome and the genome is further packed by an envelope which is associated with three structural proteins: membrane protein (M), transmembrane spike protein (S), and envelope protein (E). The heavily glycosylated S protein is post-translationally cleaved by mammalian furin into two subunits, S1 and S2; the S1 subunit contains an amino N terminal domain (NTD) and a receptor-binding domain (RBD) that binds to the host cell surface angiotensin-converting enzyme 2 receptor (ACE2) while the S2 subunit is responsible for the host-virus membrane fusion. The spike protein transiently undergoes conformational changes under the influence of furin which results in a hinge like lifting of RBD (so-called "open" conformation) which facilitates ACE2 binding (reviewed in 1 ). SARS-CoV-2 infects host cells through this attachment of S1 to ACE2 followed by fusion of the viral envelope and host cell mediated by S2.
Antibodies to structural proteins of SARS-CoV-2 are induced following natural infection. 2 Serum IgM and IgA appear earlier than IgG, peak between 2-and 5-week post-infection and then decline with IgA persisting longer than IgM. IgG peaks slightly later (3-7 weeks post-symptom onset) and then persists. 3 Concentrations of all isotypes correlate with severity of disease; the highest concentrations are seen in those with severe disease and the lowest concentrations in those with asymptomatic infection. 4,5 Neutralizing antibodies are detectable within seven to 15 days following disease onset, with levels increasing until days 14-22 before leveling off and then decreasing, but titers are lower in those with asymptomatic or clinically mild disease. Ninety percent of antibodies derived from serum or plasma of individuals infected with SARS-CoV-2 which have neutralizing activity are targeted at the spike RBD. 6 Analysis of the crystal structure of RBD-bound antibody revealed that steric hindrance inhibited viral engagement with ACE2, thereby blocking viral entry. 7 The most potent neutralizing antibodies were the most competitive with ACE2, indicating that blocking the interaction between RBD and ACE2 is a useful surrogate for neutralization. Detailed analysis of neutralizing antibody interaction with the RBD has revealed that ACE2 blocking antibodies can bind spike and RBD in both open and closed conformations while some antibodies bind RBD but do not block ACE2 and a 4th class of neutralizing antibody bind outside of the ACE2 blocking site, but only in the open confirmation. 8 Although RBD is immunodominant, there is evidence for a substantial role of other spike regions in antigenicity, most notably the N terminal domain (NTD). NTD antibodies may also have neutralizing activity; McCallum and colleagues identified a "supersite" on the NTD that was recognized by all NTD-specific neutralizing monoclonal antibodies derived from memory B cells isolated from 3 survivors of SARS-CoV-2 infection. 9 The mechanism of neutralization by which NTD-specific antibodies act remains to be fully determined, although it may involve the inhibition of conformational changes 10 or interaction with C type lectins such as DC-SIGN, L-SIGN, and SIGLEC1. 11 Recent reports also suggest that antibodies directed at the NTD may enhance the infectivity of the virus by inducing the open conformation of RBD, thus enhancing the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2 12 although such in vitro enhancement of infection does not necessarily translate into enhanced infection in vivo. 13 The potency of neutralizing antibodies has been shown to be a predictor of survival in patients with COVID-19. 14 The presence of neutralizing antibodies induced by a previous infection has also been shown to provide robust protection to subsequent reinfection with the same strain. 15 ACE2 receptor inhibition assays as a surrogate for neutralization and pseudo-virus neutralization assays utilizing pseudo-typed viruses transfected with SARS-CoV-2 spike protein, that do not require BSL3 laboratories for the handling of live virus have contributed to the description of the role of neutralizing antibodies and disease. 16 Mutations can occur in any region of the SARS-CoV-2 genome although most do not modify the primary amino acid sequence and hence the function of the translated proteins or viral infectivity.
However, a single mutation, or a combination of mutations, can yield variants with selective and survival advantages and improved viral fitness and several variants of concern (VOC) have spread worldwide. The first VOC, designated Alpha by the WHO (B.1.1.7 lineage) demonstrated increased transmissibility and had several mutations in the spike protein including D614G, N501Y and deletions DH69/ DV70. The RBD N501Y mutation was shown to increase the binding affinity for the ACE2 receptor 17 although antibody binding and neutralizing activity induced by previous infection or vaccine was generally preserved. 18 The Beta VOC (B.1.351) emerged in South Africa in October 2020 with several structural and non-structural mutations, including three critical mutations in the RBD of the S protein (K417N, E484K, and N501Y). These seemed to play a crucial role in the improved "viral fitness" and survival adaptations compared to the other strains and reduced binding of neutralizing antibodies to spike. 19 In late 2020, the Delta variant (B. although in total has more than 50 mutations with more than 30 identified in the S gene alone. 21 These mutations are associated with enhanced infectivity and transmissibility, and Omicron has also been shown to escape neutralization by monoclonal antibodies, convalescent serum, and post-vaccine antibody. 22 Overall, with the exception of the Alpha VOC, the emerging VOCs have been associated with reductions in neutralizing activity of antibodies derived from previously infected or individuals who have undergone primary vaccination [23][24][25][26] while Omicron VOC also appears to escape the neutralizing activity of most, but not all of the therapeutic antibodies currently available. 27 Interestingly, a booster dose of mRNA vaccines has been shown to largely restore neutralization activity against wild type, Delta, and Omicron. 28 The mechanism behind this enhanced functionality has been shown to be due to the third dose expanding memory B clone present after the second dose as well as stimulating new clones both of which showed increased potency and breadth due to targeting more conserved areas of the RBD. 29,30 The study of the persistence of antibodies post-infection has been complicated by the lack of standardization of antibody assays, differences in sensitivity and specificity of commercially available assays and the characteristics of patients studied. Nevertheless, consensus has emerged that nucleocapsid antibodies decline faster than those specific for spike or RBD, with the latter persisting for up to 13 months following infection 26,31,32 and models suggesting years of persistence. 33 Key to long-term protection is the persistence of neutralizing rather than just binding antibody and in general while titers decline in the months following infection, neutralizing and binding antibodies correlate well with each other. 26,32 Gallias and colleagues demonstrated that healthcare workers who were infected with the original Wuhan strain retained neutralizing activity against the D614G and alpha variants but reduced titers to the beta variant of concern. Moriyama and colleagues 34 showed that despite a decline in IgG to RBD following infection, the ability of convalescent serum to neutralize variants of concern (beta and gamma) improved in the months after infection suggesting a temporal maturation of neutralizing antibody that was attributed to affinity maturation of anti-RBD antibody. It is unclear if this improvement extends to newer variants, and specifically Omicron which has infected individuals with previous natural or vaccine-induced immunity. Infection, however, has in general been relatively mild with Omicron reinforcing the notion that immunity other than that mediated by antibody is required for modulating disease.
Antibody to SARS-CoV-2 has been identified in urine, feces, upper and lower respiratory trach secretions and in sputum although the role of mucosal immunity has not been as extensively studied as that of serum-based immunity but is likely to be important for rationally designing vaccines that provide maximal protection against mucosal pathogens. Chan and colleagues studied pediatric and adult COVID-19 patients and were able to show spike-specific IgA in the nasal epithelial lining fluid which appeared to inversely correlate with severity of disease; those with mild disease having higher titers of neutralizing antibody within the first week of illness. 35 A protective role for IgA has also been postulated by Hennings and colleagues who found healthcare workers who did not contract COVID-19 had higher serum IgA specific for spike protein although they did not study mucosal antibody. 36  infection using data from vaccinated and convalescent cohorts. They were able to demonstrate that neutralization levels are highly predictive of immune protection although this relation would likely be slightly reduced to variants. They were also able to predict a decline in vaccine-induced immunity over time. Earle and colleagues 42 using similar modeling confirmed the relationship between neutralizing titers and vaccine efficacy and demonstrated in addition that binding antibodies to spike were highly predictive of protection although, due to the lack of standardization of assays, the ratio of vaccineinduced antibody to convalescent antibody was used as a readout IgG as well as neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. 46 Higher levels of all immune markers were correlated with a reduced risk of symptomatic but not asymptomatic infection. Levels of binding F I G U R E 1 Correlation between antibody responses and efficacy rate for 7 COVID-19 vaccines. Panels A and B display correlations of antibody responses for neutralization and ELISA assay ratios, respectively, normalized to HCS panel titers from the same assay. Dot size corresponds to the number of cases reported for Phase III efficacy analyses. The y-axis is estimated log risk ratio reported on the vaccine efficacy scale. The x-axis is ratio of the peak geometric mean neutralization titer or ELISA titer at 7-28 days post-vaccination, relative to HCS. Error  IgG and neutralizing activity that correlated with a vaccine efficacy of 80% against symptomatic infection were defined although because of the overlap of antibody levels between the infected and uninfected subjects no absolute threshold of efficacy could be defined. However, neutralizing titer was directly related to efficacy, indicating that antibody levels are directly related to efficacy as shown in Figure 1. The hope with the studies cited above is that data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.
The waning of vaccine-induced antibody and the observed reduction in vaccine-induced protection against infection (as distinct from disease) has raised the question of the utility of a protective threshold of anti-spike or RBD antibody when measured immediately following the completion of a priming course of vaccine although with suitably designed longitudinal serological studies a threshold of antibody that would trigger revaccination could be defined.

| MEMORY B CELL S IN PROTEC TIVE IMMUNIT Y AG AINS T COVID -19
Memory B cells do not actively secrete antibodies; they are quiescent. Memory B cell frequencies and antibody titers exhibit different kinetics in response to SARS-CoV-2 infection. 47 Since the memory B cells and plasma cells are separate immunological compartments, conditions can occur like that seen after 2-dose mRNA COVID-19 vaccination, when spike IgG titers decline substantially over 6 months but memory B cells are stable or even increasing. 48

| Fc-EFFEC TOR FUN C TION
Antibodies are bi-functional molecules, comprised of (1) two antigen-binding domains (2× Fabs) that provide specificity and can block infection and (2) a constant domain (Fc) involved in directing immune clearing effects via the recruitment of the immune system ( Figure 5). In the context of vaccine development, antibody binding and neutralizing activity are primarily evaluated to predict protection, however, for many pathogens, the Fab and Fc antibodies collaborate to achieve maximal protection against disease. 60  Fc-effector functions highlighting the importance of the Fc-effector function, rather than the Fab-activity alone, in protection from some infections. Likewise, Fc-effector function is key to the therapeutic activity of neutralizing bacterial-toxin-specific antibodies, that require both blockade of toxin action but also clearance of the toxins from the immune system. 67 However, whether both ends of the antibody are required for protection against SARS-CoV-2 has been poorly studied.
Antibodies have the ability to deploy a wide array of immune effector functions via their ability to bind to complement or Fcreceptors, which are present on all immune cells. 60 Owing to F I G U R E 3 Layered defenses against SARS-CoV-2, or the "Swiss cheese" model of immunity. Multiple types of adaptive immunity with diverse mechanisms and locations likely provide layers of defense against COVID-19. Conceptually, layered defenses are like a "Swiss cheese model": even though each layer is imperfect, all together they make it highly unlikely that the pathogen breaches all of the layers of defense. were linked to protective immunity in an NHP challenge study. 76,77 Likewise, antibody Fc effector functions were observed following SARS-CoV-2 Ad26 vaccination in humans, 78 NHP, 79  of concern whereas antibodies induced via natural infection, 84,85 adjuvanted-protein immunization, 86 or adenoviral vaccination did not, 87 marking potentially distinct cross-reactive Fc-effector induction across vaccine platforms. Thus, while Fc-effector function co-evolves with binding titers across all vaccine platforms tested to date, the flexibility of the cross-variant Fc-effector response may vary across vaccine platform. These differences may be related to distinct epitope-specific immunodominance profiles elicited by the platforms (more RBD versus NTD targeting) or perhaps related to differences in affinity maturation of the humoral immune response. Along these lines, recent comparison of the BNT162b2 and mRNA1273 vaccines pointed to significant differences in the functional quality of the response even across the two mRNA vaccines that have been deployed globally, with higher spike-specific opsinophagocytic and NK cell activating, and NTD-specific Fc-receptor binding antibodies induced by the mRNA1273 vaccine. 88 Whether this is related to differences in mRNA dose, the extended interval between doses, or differences in formulation remains unclear, but tracks with enhanced real-world vaccine effectiveness noted for the mRNA1273 vaccine, 89 highlighting that even within a platform, antibody effector function may be tuned to enhance the generation of more functional antibodies. Collectively, the data clearly point to a critical need to define epitope-specific Fc-effector specificities to fully dissect and define the minimal functional footprints that may play a vital role in protective immunity.
Opsonophagocytic, complement activating, and NK cell recruiting functions have been detected after most SARS-CoV-2 vaccines, 78,83,84 yet, whether a precise Fc-function may collaborate with neutralizing antibodies or T cells to provide complete protection remains incompletely understood. Given the striking F I G U R E 6 Antibody mechanisms of action. The cartoon depicts that potential contribution of Fab versus Fc mediated antibody functions at different antibody titers. Where neutralization alone may be sufficient to block transmission at peak titers (left). However, as titers wane, or variants evade large fractions of antibodies, the ability of antibodies to leverage immune effector functions may be vital to protection from disease differences in Fc-effector function that were elicited using distinct clinical adjuvants (SWE, alum, CpG-alum, AS37, and AS03 86

| T CELL S IN PROTEC TIVE IMMUNIT Y AG AIN S T COVID -19
While there is robust evidence for important roles of nAbs in pro- in an outpatient setting, mAb treatment clearly provided clinical benefit to those individuals, reducing the likelihood of hospitalization. 105 However, mAb treatment only reduced viral loads by fourfold in treated seronegative subjects. 105 In contrast, placebo group individuals who seroconverted on their own exhibited 1000-fold to 10,000-fold lower viral loads. 105 Given that the mAb infusions provide >100-fold higher nAb titers, there is a large discordance be- A second conceptual framework for considering protective benefits of T cells is a "layered defenses" model, sometimes colloquially referred to as a Swiss cheese model of defenses (Figure 3). This type of model can be applied to many scenarios, wherein by having a series of layers of defenses, even if the first layer of defense is incomplete, there are additional secondary layers that also provide defense, which in sum provide sufficient immunity to be highly effective, even if the first layer fails. In the case of adaptive immunity to SARS-CoV-2, the first layer is neutralizing antibodies (nAbs), with the adaptive immune system having CD4 T cells, CD8 T cells, memory B cells, and non-nAbs each providing an additional layer of defense (Figure 9), providing a diversity of mechanisms of protective immunity, some of which are more relevant in particular tissues or time windows. This conceptual framework highlights the challenges of quantifying the contributions of different aspects of adaptive immunity to COVID-19 if multiple components of immunity are present simultaneously.
Overall, as discussed below, a reasonable working model is that nAbs are important for protection against SARS-CoV-2 infection, but once infection occurs T cells are significant contributors to control and clearance of SARS-CoV-2 infection, limiting symptomatic COVID-19 and preventing hospitalization-level disease and death ( Figure 9), with the T cell functions provided by circulating and/or local tissue-resident T cells depending on the circumstances.

| T cell mechanisms of protection
There are multiple potential mechanisms by which T cells can contribute to protective immunity against infectious diseases. These are worth briefly reviewing and then addressing which mechanisms may be active in SARS-CoV-2 infections (Figure 9).

CD8 T cells recognize and kill infected cells via direct contact
and are important in many viral infections 109 (Figure 9). In those viral infections, it is not possible to fully eliminate the virus without the activity of CD8 T cells.

| T cell protection in SARS-CoV-2 infection
Available mechanisms of immunity relate to the kinetics of clinical illness. The longer the time window before clinical disease onset, the more possibilities there are for different components of adaptive immunity to contribute to protective immunity against an acute infection. 106,120 A disease that evolves slowly increases the likelihood that memory T cells could contribute to protective immunity. Importantly, One study aimed to address the relationship between T cells and control of SARS-CoV-2 infection by longitudinally tracking T cell responses and viral loads after symptom onset. 129 In that study, the presence of strong early T cell responses was correlated with mild disease and rapid viral clearance. 129 Antibodies did not exhibit the same pattern. Individuals with very few virus-specific T cells early on were associated with sustained high viral loads and the subsequent development of severe COVID-19. 129 While those are the clearest data available indicating viral control by T cells, the study did have limitations. A relatively small number of individuals were enrolled, and the study did not distinguish between CD4 T cells and CD8 T cells.

COVID-19 in humans is
Moderbacher et al. measured SARS-CoV-2-specific CD8 T cells, CD4 T cells, and nAbs in 52 individuals followed longitudinally for disease severity. 127 The study observed positive statistical associations between the presence of SARS-CoV-2-specific CD4 T cells or CD8 T cells and reduced disease severity, while no association was seen between nAbs and reduction of COVID-19 severity. 127 Furthermore, age was correlated with low frequencies of naive T cells and weak SARS-CoV-2-specific CD4 and CD8 T cell responses, 127 providing a potential causal link between age and COVID-19 severity. The data suggest that one reason age is such a major risk factor for COVID-19 is that older individuals often have significantly smaller naive T cell repertoires, and thus have more difficulty making T cell responses to new viral infections. Limitations of this study were that it did not measure viral loads, or longitudinally track T cell responses in all individuals, and the cohort was somewhat limited in size. Three independent studies also found reduced SARS-CoV-2-specific CD8 T cell responses in hospitalized patients by intracellular cytokine staining. [130][131][132] Lastly, a study assessing nucleoprotein-specific CD8 T cells found significant associations between stronger CD8 T cell responses and mild disease. 133 In contrast, a study of only hospitalized patients did not find an association, which may be due to the lack of a non-hospitalized COVID-19 comparator group. 134 Higher levels of activated CD8 T cells in blood and poor disease outcomes were observed in a subset of individuals in a different study, but virus-specific CD8 T cells were not measured. 135  Roles for T cells in animal models of COVID-19 are challenging to define because the major animal models currently in use have much faster disease progression than in humans, making any efficacy of T cells less likely to be measured. For example, in the majority of mouse and hamster models, death occurs in 6 days; whereas in humans, it is quite common to not even have the first symptoms of mild COVID-19 reported until Day 6.

| Cross-reactive memory T cells
Pre-existing cross-reactive memory CD4 T cells recognizing SARS-CoV-2 provide insights into potential T cell mechanisms of protective immunity against COVID-19. Cross-reactive memory CD4 T cells against SARS-CoV-2 have been detected in approximately 50% of uninfected individuals. 123,150,151 Many of these memory CD4 T cells were generated in response to common cold coronavirus infections earlier in life. 152 Two studies have now reported that under the controlled conditions of vaccination, subjects having preexisting cross-reactive SARS-CoV-2-spike-specific memory CD4 T cells have more robust CD4 T cell and antibody responses to COVID-19 mRNA vaccines. 153,154 These studies give direct evidence that cross-reactive T cells are biologically functional in vivo and enhance immunity. It was speculated that these cross-reactive memory CD4 T cells may provide some degree of protective immunity against COVID-19, independently of vaccination. 123,155 Epidemiological data support a reduction in severe COVID-19 among individuals with a history of common cold coronavirus infection within the previous five years. 156 The most compelling evidence for a protective role of cross-react memory T cells against COVID-19 comes from a UK healthcare worker (HCW) study. 157 During the first COVID-19 wave, HCWs were highly exposed to the virus. Many of those HCWs remained seronegative. Seronegative HCWs were found to have significantly higher frequencies of SARS-CoV-2 reactive T cells than pre-pandemic samples from other HCWs. 157 Notably, seronegative HCWs with evidence of a potential SARS-CoV-2 infection based on the IFI27 gene biomarker were individuals with significantly higher frequencies of cross-reactive memory T cells. These cross-reactive T cells were enriched in targeting the SARS-CoV-2 replication machinery, which is highly conserved between coronaviruses. Altogether, those data suggest that individuals with high levels of cross-reactive memory T cells had protective immunity that confined SARS-CoV-2 to a brief abortive infection, without seroconversion. 157 Similar HCW T cell patterns were observed in another study. 158 Altogether, the findings suggest a role for tissueresident memory T cells in protective immunity against COVID-19.

| T cell protection against reinfection
Rhesus monkeys previously infected with SARS-CoV-2 are protected against reinfection. 159,160 Notably, depletion of CD8 T cells after SARS-CoV-2 infection resulted in significantly higher viral loads upon rechallenge of the animals with SARS-CoV-2, 70 demonstrating a role for CD8 T cells in protection against reinfection.
While tissue-resident memory CD8 T cells were not directly assessed, it may be that CD8 tissue-resident memory T cells were the primary mechanism of protection in that model, given the speed of the CD8 T cell impact on viral loads within two days of rechallenge. 70 Humans infected with SARS-CoV-2 do develop immune memory and have a high level of protection against reinfection. Protection against infection with the same variant or a similar viral variant was greater than 90% against symptomatic disease in multiple studies for a period of at least 8-12 months. [161][162][163][164] However, Omicron has a high degree of antibody escape. Most individuals infected with previous variants have undetectable nAb titers against Omicron, 165 and Omicron infection of people with natural immunity to previous variants is more common. 166 While there is limited protection against detectable infection with Omicron, there is still a high level of protection against hospitalization or fatality, 166 indicating a possible role for T cells in protection against Omicron. T cell recognition of Omicron is highly retained, [167][168][169] just as it has been for recognition of all variants of concern prior to Omicron. 170 Thus, whatever protective immunity is being provided by T cells against previous variants is still being provided against Omicron.
In the context of protection against SARS-CoV-2, tissue-resident memory T cells need to be present in the epithelial layers of the nasal passages or oral cavity, or present in the epithelium of lung tissue, including bronchi and alveoli. An additional function of tissueresident memory T cells can be an alarm function, whereby memory T cells can recognize a new infection and rapidly alert other immune system branches. [171][172][173] This is potentially relevant in the context of COVID-19, as one of the defining features of SARS-CoV-2 is an unusually efficient evasion of detection by early innate immunity by SARS-CoV-2, resulting in a lengthy delay before recognition of SARS-CoV-2 infection in humans and subsequent onset of symptoms. 106 An alternative early warning system by tissue-resident memory T cells may overcome that innate immune silence.
There is a relatively long time window between SARS-CoV-2 infection and hospitalization-level disease. Thus, even if the virus gets past the nAbs and tissue-resident memory T cells at the portal of entry, there is time for additional mechanisms of protective adaptive immunity to activate and provide layers of defenses against severe COVID-19 ( Figure 3). Disease kinetics affect the likelihood that circulating memory cells contribute to viral control. Given that memory T cells can proliferate rapidly (their numbers can increase 10-fold within 24 hours), every day is a substantial increase in the possibility that a circulating memory T cell response contributes to protective immunity. This same principle of the race between memory recall kinetics and disease progression also applies to memory B cell protection.  179,180 Alternatively, minimal handling quantiferon-type whole blood IFNγ release assays (IGRA) can be implemented as higher throughput T cell assays, without distinguishing between CD4 and CD8 T cells. 181 153,169,176,184,185 Peak antibody titers thus may serve as a proxy indicator of an individual's T cell response to these COVID-19 vaccines.

| COVID-19 vaccine T cell mediated protection
Significant protective efficacy against the ancestral strain, or Alpha, was observed after a single dose of BNT162b2mRNA vaccine, even though nAbs were low or undetectable. This was reported by Pfizer as evidence of a potential role of T cells in protection from COVID-19. 186 Similar 1-dose protection data have been observed for the mRNA-1273 vaccine in humans. 187 CD4 T cells were found to be a correlate of protection against SARS-CoV-2 for the mRNA-1273 vaccine in non-human primates. 188 Spike-specific CD4 T cells expressing CD40L, IL21, or any T H 1 cytokine were all found to be significantly associated with lower viral loads in BAL and/or nasal swabs (e.g., reported P = 0.000, 0.000, and 0.001). 188 All three of these spike-specific CD4 T cell populations were still associated with protective immunity when also considering spike-specific IgG titers in multivariate analysis. The CD4 T cell and antibody responses showed evidence of linkage, which was expected as the CD4 T FH cell response was required for the antibody responses. A separate consideration, as noted above, is that the rhesus monkey model is a challenging model to observe T cell protective immunity, as the kinetics of the infection are faster and shorter than human clinical disease. Additionally, the monkeys were challenged with 800,000 PFU of the WA1 strain, 188 whereas the 50% infectious dose in humans is 10 PFU. 189 Thus, it could be considered impressive that any impact was observed between vaccine CD4 T cells and lower viral loads.
Limitations of the study were that the T cell and antibody responses are linked and the role of the T cells could not be independently demonstrated. 188 Additionally, CD8 T cells were measured using an assay that largely did not detect spike-specific CD8 T cells after mRNA-1273 immunization, 185 whereas other CD8 T cell assays have found that a majority of immunized humans do make CD8 T cell responses. 153 Thus, any potential association between CD8 T cell responses and protective immunity in the rhesus monkey vaccination model may have gone undetected. In a separate vaccine study, CD4 T cell responses again correlated with protection, and CD8 T cell responses exhibited even strong correlation with protection. 190   There is waning mRNA vaccine protection against detectable infection over the course of 6 months after two-dose vaccination. 164,193,194 Importantly, protection against hospitalizations and deaths was relatively stable over the same period of time. 164,192 The uncoupling of infection rates from hospitalization and fatality rates is consistent with a role of vaccine-elicited T cells in protective immunity. It has been widely suggested that this is also seen for Omicron, where after two doses of mRNA vaccine most individuals have no detectable Omicron nAbs, and yet there is still significant immunity from hospitalizations or fatalities. 166,195 This again is consistent with a meaningful role for T cells in protective immunity. However, these analyses are currently limited in terms of temporal follow-up and comparator groups.

| Long COVID
It is unknown if T cells play a role in protecting against long COVID.
There is reasonable evidence of viral RNA and protein persisting for at least 90 days in the intestines of greater than 50% of unvaccinated SARS-CoV-2-infected individuals. 196 Thus, persistent SARS-CoV-2 infection as a cause of some cases of long COVID is a reasonable hypothesis. As a corollary, it is then plausible that weak CD8 T cell responses in some individuals could be associated with persistent SARS-CoV-2 in some tissues. In one case study, an 80-year-old man had substantial viral shedding for over 90 days that was associated with an impaired CD8 T cell response but an intact CD4 T cell and nAb response. 197 The potential involvement of insufficient T cell responses and multiple other immunological concepts of long COVID need to be tested and may shed light on protective immunity against COVID-19 more broadly.

| T cell protection summary
Numerous lines of evidence point to roles of T cells in protective immunity against COVID-19. One key aspect is that the kinetics of severe COVID-19 are slow enough that a T cell recall response is likely to have sufficient time to contribute to protection before the onset of hospitalization-level disease. T cell recall can occur in 3-5 days for other infections, and T cells have evidence of protection against symptomatic influenza. Given that COVID-19 is often symptomatic after 5 days, it is quite plausible that circulating T cells could prevent or moderate symptoms of COVID-19. 106 The biggest immunological difference between protective immunity generated by SARS-CoV-2 infection compared to vaccination is mostly likely the presence of local immunity in the upper respiratory tract and lungs. There are reasonable data that local tissue-resident memory T cells are present and can limit viral replication sufficiently to moderate or prevent symptomatic disease. The most striking data are that these T cells can possibly fully prevent even seroconversion to infection. Infection generates tissue-resident T cells, but vaccination presumably does not. The durability of immunity in previously infected individuals is also consistent with roles of T cells in immunity, given the low nAb titers in many individuals. Current vaccines are not designed to elicit tissue-resident memory T cells at those tissue sites.
Thus, this local mechanism of T cell protection by previous SARS-CoV-2 infection (or cross-reactive T cells) would not be expected for current COVID-19 vaccines. A mucosal vaccine would be required to generate local T cell immunity after immunization.

| DISCUSS ION
The identification of correlates of protection by vaccines requires understanding of the utility of correlates for enabling predictions but also the limitation that the immune system is complex and that CoPs We know that antibody titers fall rapidly after vaccination, which allows vaccines to again become susceptible to infection and symptomatic disease, suggesting that long-lived plasma cells are not well produced by current vaccination. The result is that reinfection is common, although cellular immunity usually prevents serious disease. Thus, the ideal vaccine would generate neutralizing antibodies as well as both CD4 + and CD8 + T cells. Ideally, B cell memory and resident plasma cells would be generated to guarantee long-term immunity.
The functionality of antibodies is also important. While antibodies are generally tested for neutralization against a fixed quantity of virus in the laboratory, protection against larger quantities of virus may be needed if a virus variant generates a higher challenge dose and therefore is more likely to overcome antibody on the mucosal surface. Human challenge studies suggest that only small amounts of viable virus are needed for infection. 198 Knowledge concerning SARS-CoV-2 mucosal antibody of either IgG or IgA class is insufficient.
The ideal vaccine against COVID-19 disease would generate high levels of neutralizing antibodies, Fc Effector antibodies, and T cells of both the CD4 + and CD8 + type, all broadly active against virus variants and maintained for long periods. At the moment, we lack such a vaccine. mRNA vaccines do elicit high levels of neutralizing and Fc effector antibodies after two doses, but those responses fade with time, and although third dose gives powerful increases of antibody height and breadth, those boosts do not necessarily persist.
It should be noted that such a defect is common with other mucosal pathogens, and it may be that repeated doses of vaccines against COVID-19 will be necessary to maintain protection against infection. That being said, epidemiological evidence to date is that protection against serious and fatal disease is much easier to achieve even if vaccines do not induce long-lasting plasma cells and thus durable antibody production.