Novavax's updated XBB.1.5 vaccine shows promising cross-neutralizing antibodies against new COVID-19 variants

By Vijay Kumar MalesuSep 5 2023

In a recent study submitted to the bioRxiv* preprint server, a group of researchers assessed the efficacy of a monovalent XBB.1.5 spike protein vaccine (Novavax, Inc.) in generating cross-neutralizing antibodies and robust immune responses, supporting its adoption as the updated Coronavirus Disease 2019 (COVID-19) vaccine for the 2023-2024 campaign.

Study: XBB.1.5 Spike Protein COVID-19 Vaccine Induces Broadly Neutralizing and Cellular Immune Responses Against EG.5.1 and Emerging XBB Variants. Image Credit: Naeblys / Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Before the recommendation for a COVID-19 vaccine was made, immunization options included the monovalent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) prototype and the bivalent version with Omicron BA.4/5. Decreased immunity against Omicron XBB variants led to updates supported by the World Health Organization (WHO), European Medicines Agency (EMA), and Food and Drug Administration (FDA) for 2023-2024 boosters. 

This emphasizes the importance of evaluating emerging Omicron XBB variants. Novavax's vaccine uses the full-length recombinant spike protein, improving antigen uptake. Produced using a specific method, the antigen particles, combined with the Matrix-M adjuvant, have shown strong responses in tests. Concerns arise from the rapid evolution of SARS-CoV-2, making continuous evaluation and updates crucial.

About the study

The present study utilized several vaccine constructs, including SARS-CoV-2 prototype rS (BV2373), as well as Omicron BA.5, XBB.1.5 rS, and XBB.1.16 rS (BV2540, BV2601, and BV2633), manufactured by the Novavax Discovery Group. The Prototype rS was derived from the wild-type SARS-CoV-2 S glycoprotein, with modifications to enhance protease resistance and stabilize the protein in a prefusion conformation. Additional amino acid substitutions were made to optimize the presentation of neutralizing epitopes, while the other rS constructs were designed based on specific variants, incorporating multiple mutations to resemble Omicron sub-variants.

For the pseudovirus neutralization (pVN) assays, SARS-CoV-2 pseudoviruses were produced using a lentivirus platform, incorporating various spike protein sequences. The pVN assay was conducted using Human Embryonic Kidney 293T (HEK293T) cells expressing human Angiotensin-Converting Enzyme 2 (hACE2), and serum samples were serially diluted before exposure to pseudovirus, generating neutralization curves and calculating 50% pVN titers (pVN50) and 50% inhibition dilution (ID50).

The cellular assay involved analyzing murine splenocytes and Non-Human Primate Peripheral Blood Mononuclear Cells (NHP PBMCs) for cytokine-producing Cluster of Differentiation 4 Positive T Lymphocyte (CD4+ T) cells. Cells were stimulated with Novavax COVID-19 Vaccine (NVX-CoV2373) or specific variant spike proteins, and intracellular cytokine staining was performed to assess the cellular responses.

Animal studies were conducted following ethical guidelines, and protocols were approved by relevant Institutional Animal Care and Use Committees (IACUCs). Mouse studies involved immunization with different vaccine formulations, with serum and spleen samples collected for subsequent analysis. NHP studies were carried out using rhesus macaques, with similar immunization and sampling protocols, to evaluate vaccine responses.

Statistical analysis involved calculating geometric mean titers (GMT) and 95% confidence intervals (95% CI) using GraphPad Prism software, facilitating the interpretation of antibody responses. Overall, the study encompassed various aspects of vaccine constructs, immunization protocols, pseudovirus neutralization assays, cellular responses, and ethical considerations to provide comprehensive insights into vaccine effectiveness.

Study results 

This study examined the results of primary immunization with various vaccine formulations in mice and assessed humoral immune responses in female  Bagg Albino Like inbred strain c (BALB/c) mice following a two-dose primary series of monovalent and bivalent vaccines. Mice were administered XBB.1.5 (1 µg rS) or bivalent rS (0.5 µg Prototype rS + 0.5 µg XBB.1.5 rS) on days 0 and 14, and serum samples were collected on day 21 after the second dose. The monovalent XBB.1.5 vaccine demonstrated advantages, eliciting comparable cross-reactive pseudovirus neutralizing antibodies (pVNAs) against XBB.1.5, XBB.1.16, and XBB.2.3, while the bivalent vaccine showed lower responses to these sub-variants.

Further evaluation was conducted after immunization with a primary series of different monovalent rS constructs. Mice were inoculated with Prototypes, XBB.1.5, or XBB.1.16 on days viz. 0 and 14, and serum samples were collected on day 21. Both XBB.1.5 and XBB.1.16 primary series induced comparable and highly immunogenic responses, generating pVNAs against multiple XBB sub-variants.

The impact of boosting was investigated in mice primed with bivalent rS followed by a booster dosage of monovalent XBB.1.5 or XBB.1.16, which induced substantial increases in pVNAs against their respective sub-variants.

Similar assessments were made in NHPs, where rhesus macaques received a primary series of prototype or bivalent vaccines and were subsequently boosted with XBB.1.5. The boosted XBB.1.5 vaccine induced comparable pseudovirus-neutralizing responses against various XBB sub-variants. 

The study also investigated CD4+ T cell responses and found that mice immunized with Prototype or bivalent priming series and boosted with XBB.1.5 exhibited robust CD4+ T cell responses, regardless of the priming vaccine. Similarly, NHPs primed with the bivalent vaccine and boosted with XBB.1.5 exhibited T-helper 1(Th1) biased cellular responses with consistent magnitudes of cytokine-positive cells for all variants tested.

The study illuminated vaccine immunogenicity using mouse and NHP models, highlighting the monovalent XBB.1.5 vaccine's efficacy in generating cross-neutralizing antibodies against diverse XBB subvariants, affirming its vaccine candidacy. Additionally, it highlighted the importance of generating robust immune responses for future viral variants and provided insights into CD4+ T cell responses.

Conclusions

To summarize, the Novavax XBB.1.5 vaccine induced cross-neutralizing responses against Omicron XBB sub-variants in mice and non-human primates. Booster studies in primates showed similar neutralization against XBB.1.5, XBB.2,3, XBB.1.16, and EG.5.1, regardless of initial vaccination.

In mice, monovalent XBB.1.5 elicited stronger neutralization than a bivalent vaccine, demonstrating both humoral and cell-mediated immune responses, including functional antibodies against various pseudoviruses and a Th1-biased CD4+ response to XBB sub-variants, suggesting the Novavax vaccine should be updated to a monovalent XBB.1.5 formulation in line with regulatory recommendations to address emerging variants. The study highlights cross-neutralization and immunity mechanisms in combating SARS-CoV-2 variants.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.