Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

Abstract

Background Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). Methods COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26. COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intentionto-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. Findings Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46•7%) participants were female and 1380 (95•4%) were White, and in the BNT/ BNT-primed group 770 (53•6%) participants were female and 1321 (91•9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1•8 (99% CI 1•5-2•3) in the half VLA group to 32•3 (24•8-42•0) in the m1273 group. GMRs for wildtype cellular responses compared with controls ranged from 1•1 (95% CI 0•7-1•6) for ChAd to 3•6 (2•4-5•5) for m1273. For BN...

Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial

“…NVX has recently been the subject of a WHO Emergency Use Licence and should become available under the COVAX scheme. 42 Furthermore data for mixed schedules across platforms could help to inform the use of third-dose boosters, in addition with data from CoV-BOOST (ISRCTN12348322) 43 and the recent work by Atmar and colleagues 44 supporting use of mRNA vaccines for adenoviral-primed individuals. Such schedules could also allow avoidance of a second mRNA vaccine dose in adolescents, given concerns regarding myocarditis, and this hypothesis is being further studied in Com-COV3.…”

COV-BOOST: evidence to support rapid booster deployment

“…Predictably, soon after the UK travel ban announcement, cases of the omicron variant were reported in Europe, 7 the UK, North America, and, as of Dec 2, 2021, 25 countries in total. [8][9][10] Paradoxically, the most concerning SARS-CoV-2 variants for a highly vaccinated population would likely arise in a high transmission environment where there are high levels of vaccine coverage, such as the UK, France, or Italy, to name but a few. 11,12 New Zealand has comprehensively restricted COVID-19 numbers but only through its geographical…”

“…In The Lancet , Alasdair Munro and colleagues 10 report the outcomes of the COV-BOOST trial, which is timely and provides valuable evidence on the immunogenicity and safety of seven COVID-19 vaccines administered as boosters. This multicentre UK trial recruited 2878 healthy participants older than 30 years across 18 sites who had received either two doses of BNT162b2 or ChAdOx1 nCov-19, with no history of previous SARS-CoV-2 infection, and randomly assigned them to receive one of seven COVID-19 vaccines; namely, NVX-CoV2373 (Novavax, NVX), ChAdOx1 nCov-19 (Oxford–AstraZeneca, ChAd), BNT162b2 (Pfizer–BioNtech, BNT), VLA2001 (Valneva, VLA), Ad26.COV2.S (Janssen), mRNA1273 (Moderna, m1273), CVnCov (CureVac), three of which were also used as half doses (BNT, VLA, and NVX) or a quadrivalent meningococcal conjugate vaccine (MenACWY) as a control.…”

“…Munro and colleagues 10 report that vaccines were effective in boosting neutralising antibody and cellular responses within 28 days of administration. They also identify no safety concerns and the profiles of side-effects were similar to those seen with the primary course across all vaccines, which should inform public health messaging on boosters, or third doses, and provide reassurance.…”

Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum

“…Possessing a high starting neutralisation titre against early pandemic strains gives a higher level of neutralisation of omicron, which could be obtained by deploying third booster doses of vaccine. There is some reassurance that a third dose of a COVID-19 vaccine does indeed increase vaccine effectiveness against the omicron variant, 7 and testing of samples from Cov-BOOST 8 will provide further information on the immunology underlying this. Together, these findings will provide further understanding of the potential for a boosting strategy as a control measure for omicron infection and transmission.…”