Immunity to SARS-CoV-2 variants

Peak-based vaccine candidates, the glycoprotein essential for entry into host cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were designed within a few days of the reported sequence in January 2020. All vaccines are aimed at preventing disease. mainly (but not exclusively) by eliciting neutralizing antibodies that block nails and thus prevent the ability of SARS-CoV-2 to infect cells. The 95% efficacy of the BNT162b2 messenger RNA (mRNA) vaccine (from Pfizer / BioNTech) announced a series of results that showed that eliciting neutralizing antibodies is strongly related to disease protection in clinical trials on different vaccines. Currently, there is concern about the reduced immune protection against vaccine against emerging variants with mutations in the vein protein. On page 1152 of this issue, Muik et al. (1) found reduced induction of neutralizing antibodies from BNT62b2. However, there is likely to be sufficient efficacy to provide protection against symptomatic diseases.

Coronaviruses are very large and complex compared to other RNA viruses (about four times as large as the hepatitis A virus genome), so their replication fidelity should be higher. Despite this, if a pathogen was allowed to infect more than 100 million people, it is no surprise that serial variants emerge with a selective advantage. By the latter part of 2020, just as regulators were authorizing a series of vaccines based largely on the wild-type “Wuhan” sequence antigen, several SARS-CoV-2 “variants of concern” were detected. These variants have the transmission, pathogenicity, immune escape or a combination of all three possible.

The first series of a variety of concerns that emerged in the UK, B.1.1.7 (also called 501Y.V1), appeared in September 2020. It contains eight amino acid changes within the peak. One of these, N501Y (Asn⁵⁰¹→ Tyr), increases the affinity of the peak for its cellular target angiotensin-converting enzyme 2 (ACE2) and, together with other less well-characterized mutations, has led to improved transmission (recognized since December) and possibly increased pathogenicity. Can this variant also escape antibody-mediated immunity? Muick et al. investigated the ability of immune sera from 40 older or younger dual-dose BNT162b2 vaccine recipients to neutralize a pseudotype virus (a safe, surrogate virus designed to express a peak) that carries wild-type sequence peak or all the B.1.1.7 peak mutations. The sera have a wide range of neutralizing antibody titers, measured against the wild type vein, from about 1/50 to about 1/1200. Although there was a significant decrease in geometric mean titers for the younger (though not the older) group compared to the B.1.1.7 variant, the authors argue that based on our understanding of other respiratory viruses such as influenza virus, an overall a reduced titer of about 20% would not predict the vaccine to be effective. However, such findings confirm that the B.1.1.7 peak mutations not only affect transmission but also immune recognition.

Another study looked in detail at possible vaccine escape by B.1.1.7 (2). They considered immune sera from 23 vaccinated individuals with a mean age of 82 years, analyzed three weeks after a single dose of BNT162b2. The use of a pseudotype virus with a peak with all eight mutations resulted in a six-fold reduction in neutralization for most sera. In this older group, the ablation of functional neutralization was more pronounced in those starting with lower antibody titers against the wild-type sequence. A parallel data set for pseudotype neutralization of wild-type sequence or B.1.1.7 peak by mRNA-1273 (Moderna) or NVX-CoV2373 (Novavax) vaccinator sera, detects a more marginal decrease in activity against the variant (3).

When population variation may mean that people develop divergent neutralizing antibody titers after vaccination, the extent to which a small decrease in neutralization protects against symptomatic diseases depends to some extent on the immunogenicity of the vaccine and how much margin it leaves for protection. This issue is being addressed by analyzes of ChAdOx1 nCoV-19 (University of Oxford / AstraZeneca) in the United Kingdom (4). Although the neutralizing antibody bite at B.1.1.7 was reduced approximately ninefold (from an average of approximately 1/500 neutralizing antibody to wild-type virus), it did not affect the efficacy of the vaccine because there was no increased susceptibility to infection. not [as determined with polymerase chain reaction (PCR) testing] attributed to the variant among the 499 participants who became infected.

Although the B.1.1.7 variant has had a major impact on the exacerbation of case load and severity in many countries, there is even greater concern about variants that contain additional immune evasion mutations, especially the E484K (Glu⁴⁸⁴→ List) mutation found in the B.1.351 (501Y.V2) variant that originated in South Africa, the P.1 variant that occurs in Brazil, and sporadic examples from UK sequence that E484K on the B.1.1.7 background shows (5). That Immune Deficiency Mutations – K417N (List⁴¹⁷→ Asn), E484K and N501Y – may arise in in vitro evolutionary experiments with the culture of SARS-CoV-2 in the presence of immune sera, provide caution against suboptimal vaccination regimens (6).

Concerns about the B.1.351 variant come from analyzes of its effects on neutralization activity. The variant shows significant ablation of any virus neutralizing activity of therapeutic monoclonal antibodies (mAbs) (7). Preliminary data indicate a reduced neutralizing response in sera of ChAdOx1 nCoV-19 vaccines and reduced efficacy to prevent mild to moderate COVID-19 (8). This supports the view that neutralizing antibody titer is the key correlate of protection (CoP). Although analysis based on the loss of in vitro neutralizing activity by individual mAbs representing the three dominant classes of epitopes at peak, provides strong evidence for immunodeficiency by the variant, the effect is less pronounced at the level of polyclonal immune serum after recovery or vaccination. This suggests that the neutralizing repertoire is broader and more resilient than has been documented so far.

Findings from studies with mAbs provide a warning for their therapeutic use, given their vulnerability to the loss of individual epitopes and also their ability to promote different variants that may prevent immune recognition. Of course, the other side of this argument is that detailed mapping of the neutralizing antibody epitopes in peak can facilitate the design of broad neutralizing vaccines and mAbs that can target numerous peak mutants (9). It is claimed that SARS-CoV-2 can accumulate mutations that evade immune responses (10). But as previously investigated with other viruses, such as HIV, immunodeficiency has the biological fitness cost for the virus, which tends to set an upper limit on the number of mutations that can be allowed if you have a broad, neutralizing antibody repertoire is confronted (11).

Since similar mutations occur repeatedly in peak, presumably due to confluent evolution in geographically distinct isolates, it is possible that the peak variants that provide a survival advantage for the virus will be limited and finite. Furthermore, a peak protein that mutates residues A, B and C to evade antibody recognition runs the structural risk of generating a new neutralizing epitope, D. Therefore, a finite number of iterative vaccines may target the major variants, but it will not necessarily to be reassessed annually as with influenza virus vaccinations. Seasonal “cold” coronaviruses in humans usually appear in two-year cycles, and recent data for one of these suggest that antigen depletion (mutations that undermine immune recognition) may underlie the escape of acquired immunity (12).

T cell immunity is likely to function as an additional COP against COVID-19 (13). The CD4⁺ and CD8⁺ T cell response includes specificity for several hundred epitopes across the entire SARS-CoV-2 proteome, most of which are intact in the variants (14, 15). Even the T cell epitopes that change in the SARS-CoV-2 variant will in most cases bind to the various human leukocyte antigen (HLA) molecules that confer antigenic peptides to T cells, although binding affinities may be altered. It will be useful to investigate whether T immunity is altered by the SARS-CoV-2 variant.

The assessment of variants on neutralization is complicated by the variability of pseudotype tests used in these studies. It would be useful to use live virus in vitro neutralization assays as internationally comparable reference points. As always, these are discussions that need to be linked to a sense of CoP values. Although much debated, many researchers feel that people with a neutralizing antibody IC₅₀ (half maximum inhibitory concentration) greater than ∼1 / 100 serum dilution would probably be safe against infection, or at least against symptomatic infection. As these are very powerful vaccines that often cause neutralizing antibody reactions with IC₅₀ of at least 1/1000, there is hopefully a reasonable safety margin before reduced recognition of variants means that effective protection is lost (see figure). Ultimately, the best defense against the emergence of further variants of concern is a rapid, global vaccination campaign – in conjunction with other public health measures to prevent transmission. A virus that cannot transmit and infect others has no chance of mutating.