Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors

Tan, Chee Wah; Chia, Wanni; Young, Barnaby Edward; Zhu, Feng; Lim, Beng Lee; Sia, Wan Rong; Thein, Tun-Linn; Chen, Mark; Leo, Yee‐Sin; Lye, David C.; Wang, Lin‐Fa

doi:10.1056/nejmoa2108453

Cited by 193 publications

(178 citation statements)

References 25 publications

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“…We found that the strong pre-CRA group was more likely to produce higher antibody responses at some of the epitopes, such as S574-603 and S1106-1125. Consistent with previous evidence, vaccinees who were previously infected with SARS-CoV or SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccinees (37)(38)(39)(40)(41)(42). However, upon analysis of the global profiles of antibody responses to the S protein peptides, the strong pre-CRA and weak pre-CRA groups showed similar patterns in response to IgG or IgM antibodies.…”

Section: Discussionsupporting

confidence: 85%

Pre-Existing Cross-Reactive Antibody Responses Do Not Significantly Impact Inactivated COVID-19 Vaccine-Induced Neutralization

et al. 2021

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Recent exposure to seasonal coronaviruses (sCoVs) may stimulate cross-reactive antibody responses against severe acute respiratory syndrome CoV 2 (SARS-CoV-2). However, previous studies have produced divergent results regarding protective or damaging immunity induced by prior sCoV exposure. It remains unknown whether pre-existing humoral immunity plays a role in vaccine-induced neutralization and antibody responses. In this study, we collected 36 paired sera samples from 36 healthy volunteers before and after immunization with inactivated whole-virion SARS-CoV-2 vaccines for COVID-19, and analyzed the distribution and intensity of pre-existing antibody responses at the epitope level pre-vaccination as well as the relationship between pre-existing sCoV immunity and vaccine-induced neutralization. We observed large amounts of pre-existing cross-reactive antibodies in the conserved regions among sCoVs, especially the S2 subunit. Excep t for a few peptides, the IgG and IgM fluorescence intensities against S, M and N peptides did not differ significantly between pre-vaccination and post-vaccination sera of vaccinees who developed a neutralization inhibition rate (%inhibition) <40 and %inhibition ≥40 after two doses of the COVID-19 vaccine. Participants with strong and weak pre-existing cross-reactive antibodies (strong pre-CRA; weak pre-CRA) had similar %inhibition pre-vaccination (10.9% ± 2.9% vs. 12.0% ± 2.2%, P=0.990) and post-vaccination (43.8% ± 25.1% vs. 44.6% ± 21.5%, P=0.997). Overall, the strong pre-CRA group did not show a significantly greater increase in antibody responses to the S protein linear peptides post-vaccination compared with the weak pre-CRA group. Therefore, we found no evidence for a significant impact of pre-existing antibody responses on inactivated vaccine-induced neutralization and antibody responses. Our research provides an important basis for inactivated SARS-CoV-2 vaccine use in the context of high sCoV seroprevalence.

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Section: Discussionsupporting

confidence: 85%

Pre-Existing Cross-Reactive Antibody Responses Do Not Significantly Impact Inactivated COVID-19 Vaccine-Induced Neutralization

et al. 2021

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“…Furthermore, in such settings, it is conceivable that low selection stringency may allow rare precursor B cells, such as those leading to broadly neutralizing antibodies, to get selected ( 42 , 75 ). With SARS-CoV-2, the spike protein appears reasonably conserved across variants ( 76 ), and has allowed the design of vaccines that can generate antibodies with pan-sarbecovirus neutralizing activity ( 77 , 78 ). Thus, incorporating diverse antigens and inter-clonal competition are expected not to affect our qualitative inferences regarding SARS-CoV-2 vaccines.…”

Section: Discussionmentioning

confidence: 99%

Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

et al. 2021

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The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

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“…To reach this target, our modelling results suggest that the vaccination programme would need to be extended to children aged 3-11 years, and vaccine efficacy against the infection would need to be >84%, in line with the efficacy estimated for the mRNA-1273 (Moderna) vaccine [9]. China is currently attempting to develop mRNA vaccines [55], vaccines that specifically target the Delta variant [56], multi-valent vaccines, and universal vaccines [57][58][59]. However, whether such vaccines will become available in the short term is unknown.…”

Section: Discussionmentioning

confidence: 77%

“…multi-valent vaccines, and universal vaccines [57][58][59]. However, whether such vaccines will become available in the short term is unknown.…”

Section: Discussionmentioning

confidence: 99%

Projecting the transition of COVID-19 burden towards the young population while vaccines are rolled out: a modelling study

Cai

Yang

Deng

et al. 2021

Preprint

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SARS-CoV-2 infection causes most cases of severe illness and fatality in older age groups. In China, over 85% of individuals aged ≥12 years have been vaccinated against COVID-19 (albeit with vaccines developed against historical lineages), while children aged 0-11 years are currently not eligible for vaccination (as of September 2021). The aim of this work is to assess whether the importation of Delta variant infections will shift the COVID-19 burden from adults to children. We developed an age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission dynamics to simulate the epidemics triggered by the importation of Delta variant infections and project the age-specific incidence of SARS-CoV-2 infections, cases, hospitalisations, intensive care unit (ICU) admissions, and deaths. In the context of the vaccination programme targeting individuals aged ≥12 years (as of September 2021), and in the absence of non-pharmaceutical interventions, the importation of Delta variant infections could lead to widespread transmission and substantial disease burden in mainland China, even with vaccination coverage as high as 97% across the currently eligible age groups. The symptomatic SARS-CoV-2 infections and hospitalisation are projected to shift towards children and young adolescents, with 13% of symptomatic infections and 30% of hospitalisations occurring in those aged 0-11 years. Extending the vaccination roll-out to include children aged 3-11 years is estimated to dramatically decrease the burden of symptomatic infections and hospitalisations within this age group (54% and 81%, respectively), but would have a low impact on protecting infants (aged 0-2 years). Our findings highlight the need to strengthen vaccination efforts by simultaneously extending the target population and elevating vaccine effectiveness.

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Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors

Cited by 193 publications

References 25 publications

Pre-Existing Cross-Reactive Antibody Responses Do Not Significantly Impact Inactivated COVID-19 Vaccine-Induced Neutralization

Pre-Existing Cross-Reactive Antibody Responses Do Not Significantly Impact Inactivated COVID-19 Vaccine-Induced Neutralization

Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

Projecting the transition of COVID-19 burden towards the young population while vaccines are rolled out: a modelling study

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