Persistence of immunity and impact of third dose of inactivated COVID-19 vaccine against emerging variants

Abstract

This is a comprehensive report on immunogenicity of COVAXIN^® booster dose against ancestral and Variants of Concern (VOCs) up to 12 months. It is well known that neutralizing antibodies induced by COVID-19 vaccines wane within 6 months of vaccination leading to questions on the effectiveness of two-dose vaccination against breakthrough infections. Therefore, we assessed the persistence of immunogenicity up to 6 months after a two or three-dose with BBV152 and the safety of a booster dose in an ongoing phase 2, double-blind, randomized controlled trial (ClinicalTrials.gov: NCT04471519). We report persistence of humoral and cell mediated immunity up to 12 months of vaccination, despite decline in the magnitude of antibody titers. Administration of a third dose of BBV152 increased neutralization titers against both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, Delta Plus and Omicron) with a slight increase in B cell memory responses. Thus, seronversion rate remain high in boosted recipients compared to non-booster, even after 6 months, post third dose against variants. No serious adverse events observed, except pain at the injection site, itching and redness. Hence, these results indicate that a booster dose of BBV152 is safe and necessary to ensure persistent immunity to minimize breakthrough infections of COVID-19, due to newly emerging variants.Trial registration: Registered with the Clinical Trials Registry (India) No. CTRI/2021/04/032942, dated 19/04/2021 and on Clinicaltrials.gov: NCT04471519.

Figure 1

Study flow chart.

Figure 2

Persistence of T and B cell memory responses against SARS-CoV-2 (D614G). Boxes display the SARS-CoV-2-specific T and B cell memory responsesafter two doses of BBV152 on Days 0 and 28 measured on Day 215 (before booster dose) and Day 243 (28 days after the booster dose of BBV152). PBMC samples collected from 15 participants (n = 8 non-booster and n = 7 BBV152 recipients). Boxes indicate upper and lower quartiles,lines within the box indicate median and whiskers extending from the boxes indicate the upper and lower quartiles.*p < 0.05, **p < 0.01, ***p < 0.005 and ****p < 0.0001.

Figure 3

Vaccine-induced antigen-specific antibody (IgG and IgA) secreting memory B-cell responses performed by ELISpot assay. PBMCs collected from vaccinated subjects on Day 215 were pre-activated or pre-stimulated with polyclonal expansion using Poly B stimulant for 4 days, with unstimulated cells or cells without pre-activation as negative controls. Antibody-secreting cells (ASC) were detected with anti-human IgG (biotin) and anti-human IgA (FITC) antibody followed by streptavidin–ALP and FITC-HRP respectively. Boxes indicate upper and lower quartiles, lines within the box indicate median and whiskers extending from the boxes indicate the upper and lower quartiles.

Figure 4

Persistence of SARS-CoV-2 antigen recall T cell responses until 12 months post 2nd dose and increased memory B cell response with the booster dose. PBMCs collected on Day 395 were used for both the assays.