Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality worldwide. Community-level immunity, acquired through infection or vaccination, is necessary to control the pandemic as the virus continues to circulate (1). mRNA vaccines encoding a stabilized version of the full-length SARS-CoV-2 Spike protein have been widely administered and clinical trial data demonstrated up to 95% efficacy in preventing symptomatic COVID-19 (2, 3). These mRNA vaccines induce potent humoral immune responses, with neutralizing antibody titers proposed as the major correlate of protection (4-6). Current evidence suggests that circulating antibodies persist for at least 6 months post-vaccination (7), though there is some decay from peak levels achieved after the second dose. This decline from peak antibody levels may be associated with an increase in infections over time compared to the initial months post-vaccination (8, 9). Yet, vaccine-induced immunity remains highly effective at preventing severe disease, hospitalization, and death even at later timepoints when antibody levels may decline (10)(11)(12).Previous research has largely focused on responses early in the course of vaccination, with transcriptional analysis identifying potential links between myeloid cell responses and neutralizing antibodies (13).

No abstract

Public T-cell responses, in which T cells bearing identical T-cell receptors (TCRs) are observed to dominate the response to the same antigenic epitope in multiple individuals, have long been a focus of immune T-cell repertoire studies. However, the mechanism that enables the survival of a specific TCR from the diverse repertoire produced in the thymus through to its involvement in a public immune response remains unclear. In this Opinion article, we propose that the frequency of production of T cells bearing different TCRs during recombination has an important role in the sharing of TCRs in an immune response, with variable levels of 'convergent recombination' driving production frequencies.

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.

SummaryThe C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.

Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched individuals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIV SF162P3 . Another challenge virus, SHIV mn229 , previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.

Public responses where identical T cell receptors (TCRs) are clonally dominant and shared between different individuals are a common characteristic of CD8 ؉ T cell-mediated immunity. Focusing on TCR sharing, we analyzed Ϸ3,400 TCR ␤ chains (TCR␤s) from mouse CD8 ؉ T cells responding to the influenza A virus D b NP366 and D b PA224 epitopes. Both the ''public'' D b NP366-specific and ''private'' D b PA224-specific TCR repertoires contain a high proportion (Ϸ36%) of shared TCR␤s, although the numbers of mice sharing TCR␤s in each repertoire varies greatly. Sharing of both the TCR␤ amino acid and TCR␤ nucleotide sequence was negatively correlated with the prevalence of random nucleotide additions in the sequence. However, the extent of TCR␤ amino acid sequence sharing among mice was strongly correlated with the level of diversity in the encoding nucleotide sequences, suggesting that a key feature of public TCRs is that they can be made in a variety of ways. Using a computer simulation of random V(D)J recombination, we estimated the relative production frequencies and variety of production mechanisms for TCR␤ sequences and found strong correlations with the sharing of both TCR␤ amino acid sequences and TCR␤ nucleotide sequences. The overall conclusion is that ''convergent recombination,'' rather than a bias in recombination or subsequent selection, provides the mechanistic basis for TCR sharing between individuals responding to identical peptide plus MHC class I glycoprotein complexes.diversity ͉ repertoire ͉ selection ͉ public response T he immune T cell repertoire selected in response to any given peptide plus MHC class I glycoprotein (pMHCI) can be dominated by ''public'' T cell receptors (TCRs), defined on the basis of amino acid sequence identity in multiple individuals (1, 2). Such public TCRs have been observed in a variety of antigen-specific CD4 ϩ and CD8 ϩ T cell responses in different species (1-6). The recurrent contribution of identical TCRs to immune responses in different individuals is intriguing, given the possible extent of the TCR repertoire. For example, the potential size of the TCR repertoire in mice is Ͼ10 15 (7), which greatly outnumbers both the total number of T cells (Ϸ10 8 ) and the size of the actual (8) murine TCR ␣/␤ chain (TCR␣/␤) repertoire in a mouse (Ϸ10 6 ).Various explanations have been advanced to explain the prevalence of public TCRs in different immune responses. Early studies proposed that the need to maintain self tolerance to peptides with significant self homology restricts the capacity of TCRs to recognize some epitopes (1). More recently, peptide conformations in the MHCI groove that are flat (''vanilla;'' refs. 9 and 10) or very prominent (''hot and spicy; '' refs. 11 and 12) in the way they present to the TCR or unusual structural features of the public TCR and its interactions with pMHCI that somehow provide a high functional avidity (13) have been suggested as causes of public TCRs. Public TCRs may also be characterized by readily formulated near-germ-line recomb...