Neutralising antibody responses to SARS-CoV-2 omicron among elderly nursing home residents following a booster dose of BNT162b2 vaccine: A community-based, prospective, longitudinal cohort study

Abstract

Background: The protective immunity against omicron following a BNT162b2 Pfizer booster dose among elderly individuals (ie, those aged >65 years) is not well characterised.

Methods: In a community-based, prospective, longitudinal cohort study taking place in France in which 75 residents from three nursing homes were enrolled, we selected 38 residents who had received a two-dose regimen of mRNA vaccine and a booster dose of Pfizer BNT162b2 vaccine. We excluded individuals that did not receive three vaccine doses or did not have available sera samples. We measured anti-S IgG antibodies and neutralisation capacity in sera taken 56 (28-68) and 55 (48-64) days (median (range)) after the 2^nd and 3^rd vaccine doses, respectively. Antibodies targeting the SARS-CoV-2 Spike protein were measured with the S-Flow assay as binding antibody units per milliliter (BAU/mL). Neutralising activities in sera were measured as effective dilution 50% (ED50) with the S-Fuse assay using authentic isolates of delta and omicron BA.1.

Findings: Among the 38 elderly individuals recruited to the cohort study between November 23^rd, 2020 and April 29^th, 2021, with median age of 88 (range 72-101) years, 30 (78.95%) had been previously infected with SARS-CoV-2. After three vaccine doses, serum neutralising activity was lower against omicron BA.1 (median ED50 of 774.5, range 15.0-34660.0) than the delta variant (median ED50 of 4972.0, range 213.7-66340.0), and higher among previously infected (ie, convalescent; median ED50 against omicron: 1088.0, range 32.6-34660.0) compared with infection-naive residents (median ED50 against omicron: 188.4, range 15.0-8918.0). During the French omicron wave in December 2021-January 2022, 75% (6/8) of naive residents were infected, compared to 25% (7/30) of convalescent residents (P=0.0114). Anti-Spike antibody levels and neutralising activity against omicron BA.1 after a third BNT162b2 booster dose were lower in those with breakthrough BA.1 infection (n=13) compared with those without (n=25), with a median of 1429.9 (range 670.9-3818.3) BAU/mL vs 2528.3 (range 695.4-8832.0) BAU/mL (P=0.029) and a median ED50 of 281.1 (range 15.0-2136.0) vs 1376.0 (range 32.6-34660.0) (P=0.0013), respectively.

Interpretation: This study shows that elderly individuals who received three vaccine doses elicit neutralising antibodies against the omicron BA.1 variant of SARS-CoV-2. Elderly individuals who had also been previously infected showed higher neutralising activity compared with naive individuals. Yet, breakthrough infections with omicron occurred. Individuals with breakthrough infections had significantly lower neutralising titers compared to individuals without breakthrough infection. Thus, a fourth dose of vaccine may be useful in the elderly population to increase the level of neutralising antibodies and compensate for waning immunity.

Funding: Institut Pasteur, Fondation pour la Recherche Médicale (FRM), European Health Emergency Preparedness and Response Authority (HERA), Agence nationale de recherches sur le sida et les hépatites virales - Maladies Infectieuses Emergentes (ANRS-MIE), Agence nationale de la recherche (ANR), Assistance Publique des Hôpitaux de Paris (AP-HP) and Fondation de France.

Keywords: Antibodies; Elderly individuals; Omicron; SARS-CoV-2; Vaccine.

Figure 1

Immunogenicity of a booster dose of BNT162b2 vaccine in elderly individuals. (a) Thirty-eight elderly individuals from three nursing homes, (30 females and 8 males) were included in the analysis. All received a two-dose regimen of mRNA vaccine (Pfizer BNT162b2; n=34 or Moderna; n=4) and a booster dose (Pfizer BNT162b2; n=38) 8 months apart. Thirty were diagnosed with COVID-19 prior to their booster dose. (b) Anti-Spike IgGs were measured using the S-Flow assay 2 months after the second dose and 2 months after the booster dose. Data are provided as Binding Arbitrary Unit per mL (BAU/mL), the standardised WHO unit. The limit of detection is 3 BAU/mL. Comparisons were performed using the Wilcoxon matched-pairs signed rank test. (c) Neutralisation of delta and omicron were measured using the live-virus S-Fuse assay 2 months after the second dose and 2 months after the booster dose. Data are provided as Effective Dilution 50 (ED50), indicating the dilution of serum capable of inhibiting 50% of viral infection. Green dots indicate individuals with an history of COVID-19 prior to their booster dose of vaccine. Pink dots indicate individuals with no previous COVID-19. The dashed line indicates the limit of detection. Comparisons were performed using the Wilcoxon matched-pairs signed rank test.

Figure 2

Humoral immune response predicts odds of omicron breakthrough infection. (a) Omicron breakthrough infections were reported in the 3 nursing homes included in the study, including 13 breakthrough infections among our study participants. The number of individuals included in our study, as well as the number of breakthrough infections among them are indicated for each household (A, B and C). We collected sera prior to the outbreaks (median (range) of 53 (49-60) days before the breakthrough infection, corresponding to 55 (49-59) days after the booster dose) (b) Levels of anti-Spike IgGs and neutralisation of omicron are indicated for individuals from the three households (A, B and C) having a subsequent confirmed breakthrough infection or not. (c) Levels of anti-Spike IgGs and neutralisation of omicron are indicated for individuals from the household A having a subsequent confirmed breakthrough infection or not. Data are provided as Binding Arbitrary Unit per mL (BAU/mL) (left) and neutralisation titers (ED50) (right). Comparisons were performed using the Mann-Whitney rank test. Green dots indicate individuals with an history of COVID-19 prior to their booster dose of vaccine. Pink dots indicate individuals with no previous COVID-19. The dashed line indicates the limit of detection of the neutralisation assay (30). The limit of detection of the anti-Spike assay is 3 BAU/mL. Black bars indicate the median.