Protein-based SARS-CoV-2 spike vaccine booster increases cross-neutralization against SARS-CoV-2 variants of concern in non-human primates

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that partly evade neutralizing antibodies raises concerns of reduced vaccine effectiveness and increased infection. We previously demonstrated that the SARS-CoV-2 spike protein vaccine adjuvanted with AS03 (CoV2 preS dTM-AS03) elicits robust neutralizing antibody responses in naïve subjects. Here we show that, in macaques primed with mRNA or protein-based subunit vaccine candidates, one booster dose of CoV2 preS dTM-AS03 (monovalent D614 or B.1.351, or bivalent D614 + B.1.351 formulations), significantly boosts the pre-existing neutralizing antibodies against the parental strain from 177- to 370-fold. Importantly, the booster dose elicits high and persistent cross-neutralizing antibodies covering five former or current SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, Delta and Omicron) and, unexpectedly, SARS-CoV-1. Interestingly, we show that the booster specifically increases the functional antibody responses as compared to the receptor binding domain (RBD)-specific responses. Our findings show that these vaccine candidates, when used as a booster, have the potential to offer cross-protection against a broad spectrum of variants. This has important implications for vaccine control of SARS-CoV-2 variants of concern and informs on the benefit of a booster with the vaccine candidates currently under evaluation in clinical trials.

A Beta-containing bivalent SARS-CoV-2 spike protein vaccine candidate with AS03 elicits durable and broad neutralization of variants including Omicron in macaques and confers protection in hamsters

“…Our data are in line with a previous study in mice showing lower induction of nAbs (parental, Alpha, Beta and Gamma) with heterologous vaccination with S-trimer vaccine (D614 on D0 and Beta on D21), compared to 2-doses with a bivalent vaccine 40 . The limited breadth of responses observed with the 2-doses heterologous regimen contrasts with the expanded breadth of neutralizing responses observed recently after a late booster vaccine in NHPs and humans 14,15 . This likely relates to the absence of maturation of the memory B cell population when the second injection is performed shortly after the priming immunization (3 weeks here compared to 6 months to one year in the context of a booster vaccination) 41,42 .…”

“…We recently showed that soluble prefusion-stabilized Spike trimers (CoV2 preS dTM) based on the D614 sequence formulated with the AS03 adjuvant elicited a favorable safety pro le and high immunogenicity against the parental strain in naïve adults 13 . In addition, we demonstrated that, in primed macaques, one booster dose of CoV2 preS dTM-AS03 (D614 or Beta) enhanced neutralizing antibodies against the parental virus and extended the neutralization to multiple VOC (Alpha, Beta, Gamma, Delta and Omicron) and SARS-CoV-1 14 . Preliminary data from two clinical trials assessing CoV2 preS dTM-AS03 as a booster in COVID-19 vaccine primed individuals con rmed these results and further suggested the superiority of the Beta monovalent vaccine formulations compared to D614 monovalent mRNA or subunit vaccines 15,16 .…”

“…Reporter virus particles (RVPs)-GFP used in the lentivirus-based pseudovirus neutralization assay were obtained from Integral Molecular (Table 1). (human) (NIBSC code: 20/136) have been described previously 14 .…”

“…The assay has been described previously 14 . Mu (B. Pre-stimulated PBMCs were harvested and centrifuged at 1500 rpm for 5 minutes at Room Temperature (RT).…”

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“…In addition, the platform is suitable for the developing world, because it is much cheaper and more stable than for example mRNA vaccines. We only recently started to gain more widespread clinical experience with this COVID-19 vaccine platform, for example the approved subunit vaccine Nuvaxovid ® from Novavax (Rockville, MA, United States) containing recombinant S protein formulated with the Matrix-M TM adjuvant (Heath et al, 2021), and clinical data are currently emerging for the COVID-19 vaccine from Sanofi-GlaxoSmithKline, which includes recombinant S protein formulated with the squalene oil-based adjuvant AS03 (Pavot et al, 2022).…”