mRNA vaccination in people over 80 years of age induces strong humoral immune responses against SARS-CoV-2 with cross neutralization of P.1 Brazilian variant

Abstract

Age is the major risk factor for mortality after SARS-CoV-2 infection and older people have received priority consideration for COVID-19 vaccination. However, vaccine responses are often suboptimal in this age group and few people over the age of 80 years were included in vaccine registration trials. We determined the serological and cellular response to spike protein in 100 people aged 80-96 years at 2 weeks after the second vaccination with the Pfizer BNT162b2 mRNA vaccine. Antibody responses were seen in every donor with high titers in 98%. Spike-specific cellular immune responses were detectable in only 63% and correlated with humoral response. Previous SARS-CoV-2 infection substantially increased antibody responses after one vaccine and antibody and cellular responses remained 28-fold and 3-fold higher, respectively, after dual vaccination. Post-vaccine sera mediated strong neutralization of live Victoria infection and although neutralization titers were reduced 14-fold against the P.1 variant first discovered in Brazil they remained largely effective. These data demonstrate that the mRNA vaccine platform delivers strong humoral immunity in people up to 96 years of age and retains broad efficacy against the P.1 variant of concern.

Keywords: COVID-19; human; immunosenescence; infectious disease; microbiology; vaccination.

Figure 1.. Strong antibody responses develop after vaccination with higher antibody levels seen in those with previous natural infection.

(A) SARS-CoV-2 spike (S)-specific whole antibody titer after double vaccination. Blue bars represent participants where positive nucleocapsid (N)-specific serology indicates previous natural infection. (B) Comparison of S-specific and N-specific whole antibody titer after double vaccination amongst those with natural infection (R=0.34; p=033). (C) Comparison of S-specific whole antibody titer in serum with eluate ratio from dried blood spot (DBS). Blue dots represent participants where positive nucleocapsid (N)-specific serology indicates previous natural infection (r=0.68; p≤0.0001). (D) S-specific antibody response measured by DBS after the first and second vaccine dose amongst donors with evidence of natural infection. (E) S-specific antibody response by DBS after the first and second vaccine dose amongst donors with no evidence of previous natural infection (p≤0.0001).

Figure 1—figure supplement 1.. Serum immunoglobulin isotype concentration in relation to spike-specific antibody response.

Figure 2.. Spike-specific T cell responses after vaccination.

(A) T cell responses against S1 domain and S2 domain as defined by IFNγ ELISpot assay. Black solid line indicates the median value of 32 against S1 and 28 against S2. Dotted line indicates cutoff for a positive response of 24 spots/million PBMC (n=98) (p=0.35). (B) Total spike-specific T cell responses as defined by IFNγ ELISpot assay. Black solid line indicates the median value of 84. Positive response defined as 48 spots/million (n=98). (C) T cell responses against spike by IFNγ ELISpot assay in relation to the history of previous natural infection. Blue indicates previous exposure (PE) (median 228 spots/million PBMC) and red indicates no previous exposure (NPE) (median 72 spots/million PBMC). Black solid line indicates the median value (n=98). Dotted line indicates cutoff for positive response. Solid black line indicates the median (p=0.0033). (D) T cell response against the nucleocapsid domain measured by IFNγ ELISpot assay in relation to the history of previous natural infection (p=0.049). (E) T cell response against the membrane domain measured by IFNγ ELISpot assay in relation to the history of previous natural infection (p≤0.0001). (F) Relationship of spike-specific whole antibody response by ELISA and spike-specific cellular response by ELISpot. Blue indicates PE and red indicates NPE. Dotted line indicates cutoff for ELISpot (r=0.46; p=0.000003). PBMC, peripheral blood mononuclear cell.

Figure 3.. No correlation between age and vaccine response in donors 80–96 years of age.

(A) Spike-specific whole antibody response using Roche ELISA in relation to age. Blue data points indicate previous exposure (PE) and red indicates no previous exposure (NPE) (r=–0.018; p=0.86). (B) RBD-specific IgG response (MSD) in relation to age. Blue data points indicate PE and red indicates NPE (r=–0.025; p=0.79). (C) Spike-specific cellular response by ELISpot in relation to age. Blue data points indicate PE and red indicates NPE (r=–0.009; p=0.92).

Figure 4.. Neutralization of SARS-CoV-2 variants in vitro.

(A) SARS-CoV-2 neutralization in vitro. Red bars represent neutralization against the Victoria variant and green bars show neutralization against the P.1 variant (n=20). (B) Relationship between neutralization of Victoria and P.1 variants (r=0.748; p=0.0001; n=20, respectively; p≤0.0001). (C) Correlation between spike-specific IgG titer and viral neutralization against Victoria and P.1 variants (r=0.857; p≤0.0001 and r=0.796; p≤0.0001, respectively).