Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern.

Abstract

Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK, and B1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417 escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks RBD. To address this potential threat, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort naturally infected in the first wave of the epidemic in Spring 2020. We tested antibody and T cell responses against a reference isolate (VIC001) representing the original circulating lineage B and the impact of sequence variation in these two VOCs. We identified a reduction in antibody neutralization against the VOCs which was most evident in the B1.351 variant. However, the majority of the T cell response was directed against epitopes conserved across all three strains. The reduction in antibody neutralization was less marked in post-boost vaccine-induced than in naturally-induced immune responses and could be largely explained by the potency of the homotypic antibody response. However, after a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOCs was completely abrogated in the majority of vaccinees. These data indicate that VOCs may evade protective neutralising responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine, but the impact of the VOCs on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants. We observed that two doses of vaccine also induced a significant increase in binding antibodies to spike of both SARS-CoV-1 & MERS, in addition to the four common coronaviruses currently circulating in the UK. The impact of antigenic imprinting on the potency of humoral and cellular heterotypic protection generated by the next generation of variant-directed vaccines remains to be determined.Authorship note: Donal T. Skelly and Adam C. Harding contributed equally; Miles W. Carroll and William S. James contributed equally

Increased transmission of SARS-CoV-2 lineage B.1.1.7 (VOC 2020212/01) is not accounted for by a replicative advantage in primary airway cells or antibody escape

“…Our finding is supported by many studies using B.1.1.7 viruses and PV which show either no reduction or a modest reduction in polyclonal serum titres (Collier et al, 2021;Diamond et al, 2021;Hu et al, 2021;Muik et al, 2021;Rees-Spear C et al, 2021;Wang et al, 2021;Wu et al, 2021). There is some evidence of heterogeneity of responses and neutralising titres for some individuals with initially low responses against WT virus can drop below limits of detection against the B.1.1.7 variant (Skelly et al, 2021). However, since the correlate of protection is not yet established for SARS-CoV-2, the significance of this drop is still not clear.…”

“…Against authentic SARS-CoV-2, convalescent and BNT162b2 vaccine serum titres were equivalent against a mouse-adapted strain with N501Y and the parental strain (Rathnasinghe et al, 2021), whereas a full B.1.1.7 isolate showed a two-fold reduction in neutralisation by BNT162b2 vaccine sera (Diamond et al, 2021). Others have reported a 2-fold reduction in neutralisation of authentic B.1.1.7 virus by both convalescent and BNT162b2 vaccine sera with some convalescent sera which weakly neutralise the WT virus falling below the threshold of detection against B.1.1.7 (Skelly et al, 2021). Taken together, the evidence to date shows that the B.1.1.7 variant is equivalently or slightly less well neutralised by polyclonal sera and does not yet present a substantial risk of escape from pre-existing or vaccine-induced antibody immunity.…”

Naturally-acquired immunity in Syrian Golden Hamsters provides protection from re-exposure to emerging heterosubtypic SARS-CoV-2 variants B.1.1.7 and B.1.351

“…While escape from neutralisation in vitro is an important line of evidence as to whether emerging strains will escape pre-existing immunity or not, other factors such as non-neutralising antigen-specific antibodies, T cells and innate lymphocytes clearly have the potential to contribute protection in vivo [21][22][23][24] . Indeed, recent work has shown that T cell epitopes that dominate human SARS-CoV-2 responses are not subject to major substitution in the three variants of concern 5 . Further, it is known that previous infection with influenza virus results in reduced disease against subsequent infection with heterosubtypic strains, in both human and animals, demonstrating the power of cellmediated immunity and non-neutralising antibodies in protection [21][22][23][24] .…”

An observational cohort study on the incidence of SARS-CoV-2 infection and B.1.1.7 variant infection in healthcare workers by antibody and vaccination status

“…21 Reinfection rates following natural infection have not been shown to be higher in studies using SGTF as a proxy for B.1.1.7, 20,22 even though variably decreased sensitivity to neutralisation by monoclonal antibodies, convalescent plasma and sera from vaccinated individuals has been observed in vitro for B.1.1.7. [23][24][25][26][27][28][29][30][31][32][33][34] The Oxford-AstraZeneca trial showed good vaccine efficacy against sequencingconfirmed symptomatic B.1.1.7, despite evidence of decreased neutralising titres, but decreased efficacy for asymptomatic/unknown symptom infections. 35 Pfizer-BioNTech vaccine effectiveness in HCWs appears preserved despite increasing B.1.1.7 incidence in the UK; however these studies have not specifically investigated cases of SGTF or sequencing-confirmed B.1.1.7.…”