Slower Waning of Anti-SARS-CoV-2 IgG Levels Six Months after the Booster Dose Compared to Primary Vaccination

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Abstract

Anti-SARS-CoV-2 IgG titer decreases rapidly after primovaccination, leading to a mandatory booster vaccination. We analysed anti-SARS-CoV-2 Spike RBD IgG levels (positive ≥ 50 AU/mL) in 405 healthcare workers (3010 sera) who received a booster dose (BD) 9 months after two-dose BNT162b2 primovaccination. Median antibody titer at the time of BD (582.6 AU/mL) was 1.7-fold and 16.4-fold lower than the peak titer after the first (961.5 AU/mL) and the second vaccine dose (SVD) (10,232.6 AU/mL), respectively. One month after vaccination, IgG titer increased 40.6-fold after BD compared with a 10.8-fold increase after primovaccination. Three months after vaccination, post-booster antibodies decreased significantly slower (2.2-fold) than after primovaccination (3.3-fold). At six months, antibodies decreased slower after BD (4.5-fold; median 5556.0 AU/mL) than after primovaccination (9.6-fold; median 1038.5 AU/mL). Antibody titers before and one month after BD correlated weakly (r = 0.30) compared with a strong correlation (r = 0.65) between the corresponding post-primovaccination titers. Pre-vaccination COVID-19 had no effect on IgG levels after BD compared with a positive effect after primovaccination. Despite high post-booster IgG levels, 22.5% of participants contracted mild COVID-19. The trend of IgG decline indicates the need for further revaccination, but the vaccine type should be defined according to viral mutations.

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Evolution of antibody immunity to SARS-CoV-2

Christian Gaebler, Zijun Wang, Julio C C Lorenzi … (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

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SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Christopher Barnes, Claudia A. Jette, Morgan E. Abernathy … (2020)

The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein1-5 show promise therapeutically and are being evaluated clinically6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs9. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.

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Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19

Nicole Doria-Rose, Mehul S. Suthar, Mat Makowski … (2021)

To the Editor: Interim results from a phase 3 trial of the Moderna mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine indicated 94% efficacy in preventing coronavirus disease 2019 (Covid-19). 1 The durability of protection is currently unknown. We describe mRNA1273-elicited binding and neutralizing antibodies in 33 healthy adult participants in an ongoing phase 1 trial, 2-4 stratified according to age, at 180 days after the second dose of 100 μg (day 209). Antibody activity remained high in all age groups at day 209. Binding antibodies, measured by means of an enzyme-linked immunosorbent assay against SARS-CoV-2 spike receptor–binding domain, 2 had geometric mean end-point titers (GMTs) of 92,451 (95% confidence interval [CI], 57,148 to 149,562) in participants 18 to 55 years of age, 62,424 (95% CI, 36,765 to 105,990) in those 56 to 70 years of age, and 49,373 (95% CI, 25,171 to 96,849) in those 71 years of age or older. Nearly all participants had detectable activity in a pseudovirus neutralization assay, 2 with 50% inhibitory dilution (ID50) GMTs of 80 (95% CI, 40 to 135), 57 (95% CI, 30 to 106), and 59 (95% CI, 29 to 121), respectively. On the more sensitive live-virus focus-reduction neutralization mNeonGreen test, 4 all the participants had detectable activity, with ID50 GMTs of 361 (95% CI, 258 to 504), 171 (95% CI, 95 to 307), and 131 (95% CI, 69 to 251), respectively; these GMTs were lower in participants 56 to 70 years of age (P=0.03) and in those 71 years of age or older (P=0.005) than in those 18 to 55 years of age (Figure 1; also see the Supplementary Appendix, available with the full text of this letter at NEJM.org). The estimated half-life of binding antibodies after day 43 for all the participants was 52 days (95% CI, 46 to 58) calculated with the use of an exponential decay model, which assumes a steady decay rate over time, and 109 days (95% CI, 92 to 136) calculated with the use of a power-law model (at day 119), which assumes that decay rates decrease over time. The neutralizing antibody half-life estimates in the two models were 69 days (95% CI, 61 to 76) and 173 days (95% CI, 144 to 225) for pseudovirus neutralization and 66 days (95% CI, 59 to 72) and 182 days (95% CI, 153 to 254) for live-virus neutralization. As measured by ΔAICc (change in Akaike information criterion, corrected for small sample size), the best fit for binding and neutralization were the power-law and exponential decay models, respectively (see the Supplementary Appendix). These results are consistent with published observations of convalescent patients with Covid-19 through 8 months after symptom onset. 5 Although the antibody titers and assays that best correlate with vaccine efficacy are not currently known, antibodies that were elicited by mRNA-1273 persisted through 6 months after the second dose, as detected by three distinct serologic assays. Ongoing studies are monitoring immune responses beyond 6 months as well as determining the effect of a booster dose to extend the duration and breadth of activity against emerging viral variants. Our data show antibody persistence and thus support the use of this vaccine in addressing the Covid-19 pandemic.