Persistence of immunity and impact of a third (booster) dose of an inactivated SARS-CoV-2 vaccine, BBV152; a phase 2, double-blind, randomised controlled trial

  1. Krishna Mohan Vadrevu
  2. Brunda Ganneru
  3. Siddharth Reddy
  4. Harsh Jogdand
  5. Dugyala Raju
  6. Usha Praturi
  7. Gajanan Sapkal
  8. Pragya Yadav
  9. Prabhakar Reddy
  10. Savita Verma
  11. Chandramani Singh
  12. Sagar Vivek Redkar
  13. Chandra Sekhar Gillurkar
  14. Jitendra Singh Kushwaha
  15. Satyajit Mohapatra
  16. Amit Bhate
  17. Sanjay Rai
  18. Raches Ella
  19. Priya Abraham
  20. Sai Prasad
  21. Krishna Ella
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Abstract

Background

Neutralising antibody responses to SARS-CoV-2 vaccines have been reported to decline within 6 months of vaccination, particularly against Variants of Concern (VOC). We assessed the immunogenicity and safety of a booster dose of BBV152 administered 6 months after the second of a two-dose primary vaccination series.

Methods

In an ongoing phase 2 trial (ClinicalTrials.gov: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04471519">NCT04471519</ext-link> ) the protocol was amended after six months to re-consent and randomise 184 previously vaccinated participants to receive a third dose of vaccine or placebo on Day 215. The primary outcome was to measure neutralising antibody titres by plaque-reduction neutralisation test (PRNT 50 ) four weeks after the booster; safety as serious adverse events (SAE) was the key secondary outcome.

Findings

Four weeks after a second BBV152 vaccination geometric mean titres (GMTs) of neutralising antibodies were 197·0 PRNT 50 (95% CI: 155·6–249·4); this level declined to 23·9 PRNT 50 (14·0–40·6) six months later, with a seroconversion rate of 75·4% (95% CI: 68·4–81·6). Four weeks after booster vaccination the GMT increased on Day 243 to 746·6 PRNT 50 (514·9–1081) compared with 100·7 PRNT 50 (43·6–232·6) in the placebo group. Corresponding seroconversion rates were 98·7% (92·8–99·9) and 79·8% (69·6–87·8). Increased titres in the placebo group were attributed to natural infection as the study was conducted during the second wave of COVID-19 in India. PRNT 50 titres against the SARS-CoV-2 variants increased—Alpha (32·6-fold), Beta (161·0-fold), Delta (264·7-fold), and Delta plus (174·2-fold)—after the booster vaccination. We found that vaccine induces both memory B and T cells with a distinct AIM+ specific CD4+T central and effector memory phenotype, including CD8+ T EMRA phenotype. Reactogenicity after vaccine and placebo was minimal and comparable, and no SAEs were reported.

Interpretation

Six months after a two-dose BBV152 vaccination series cell mediated immunity and neutralising antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralising antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination. Booster BBV152 vaccination is safe and may be necessary to ensure persistent immunity to prevent breakthrough infections.

Funding

This work was supported and funded by Bharat Biotech International Limited.

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