Tetravalent COVID vaccine provides broad antibody responses against SARS-CoV-2 variants in animal model

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In a recent study posted to the bioRxiv* preprint server, researchers in Italy and the United States evaluated the efficacy and immunogenicity of an adjuvanted tetravalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein subunit 1 (S1) COVID-19 vaccine.

Comprising the Wuhan-Hu-1 strain, and SARS-CoV-2 variants of concern (VOCs) Alpha, Beta, and Gamma S1 proteins, in a non-human primate (NHP) model of rhesus macaques (RM) with controlled simian immunodeficiency virus (SIV) infection.

Study: Tetravalent SARS-CoV-2 S1 Subunit Protein Vaccination Elicits Robust Humoral and Cellular Immune Responses in SIV-Infected Rhesus Macaque Controllers. Image Credit: Blue Planet Studio / ShutterstockStudy: Tetravalent SARS-CoV-2 S1 Subunit Protein Vaccination Elicits Robust Humoral and Cellular Immune Responses in SIV-Infected Rhesus Macaque Controllers. Image Credit: Blue Planet Studio / 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*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.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

Coronavirus disease 2019 (COVID-19) vaccines have effectively reduced morbidity and mortality associated with SARS-CoV-2 infections. However, the continual emergence of increasingly transmissible and immune-evasive VOCs has threatened vaccine efficacy. Therefore, updated multivalent vaccines conferring durable and broad immune protection are required to mitigate COVID-19.

Protein subunit-type COVID-19 vaccines are reportedly safe and immunogenic, with ease of mass-level production, distribution, storage, and transportation, and have demonstrated success against other viruses, such as the hepatitis B virus (HBV). The properties make the vaccine type ideal candidates for global vaccine equity, especially for nations having limited access to viral vector-based and messenger ribonucleic acid (mRNA) vaccines.

The study's authors previously demonstrated the immunogenicity of S1-targeted vaccines against several β-CoVs, including SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome-CoV (MERS-CoV).

About the study

In the present study, researchers evaluate the immunogenicity of a tetravalent SARS-CoV-2 S1 vaccine, targeting Wuhan-Hu-1, Alpha, Beta, and Gamma S1, among RMs; infected with SIV.

The team profiled lymphocyte responses to vaccination for two months following initial prime vaccination by determining B and T lymphocyte counts. They investigated T-lymphocyte activation marker levels, and memory lymphocyte subset counts among peripheral blood mononuclear cells (PBMCs). Activation markers, such as the cluster of differentiation (CD)- 38, -69, and the human leukocyte antigen-DR isotype (HLA-DR), were used for the analysis.

In addition, Ki-67 proliferation marker expression was assessed. Before vaccination, RMs were infected with SIVs that naturally infect African green monkeys (SIVsab). RMs were administered prime and booster vaccinations on week 3.0 with recombinant SARS-CoV-2 Wuhan-Hu-1, Alpha, Beta, and Gamma spike proteins, mixed with the AddaVaxTM squalene-based adjuvant. Recombinant SARS-CoV-2 proteins expressing vectors were constructed, and the plasmid constructs were confirmed by deoxyribonucleic acid (DNA) sequencing.

Subsequently, the proteins were purified and transiently expressed in Expi293 cells. Transfection experiments were performed, following which the supernatants were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot (WB) analyses. Rhesus macaques peripheral blood mononuclear cells (RM-PMBCs) were obtained on days 1.0, 3.0, 7.0, 10.0, 14.0., 21.0, 24.0, 28.0, 31.0, 35.0, 42.0, 49.0, and 64.0 days after prime vaccination. The serological anti-Wuhan-Hu-1 immunoglobulin G (IgG) antibody endpoint titers (EPT) were determined using enzyme-linked immunosorbent assays (ELISA).

Further, microneutralization assays (NT90) were performed to assess the SARS-CoV-2 neutralization ability of vaccinated RM sera. The inhibition of binding between angiotensin-converting enzyme-2 (ACE2) and SARS-CoV-2 VOCs' trimeric S proteins, including those of Omicron sub-VOCs (BA.2 sub-VOC, BA.3 sub-VOC, BA.1 sub-VOC with R246K mutation, and the BA.1 sub-VOC with L452R mutation), was assessed.

The team performed intracellular cytokine staining to assess anti-S T lymphocyte responses among hyper and cytotoxic T lymphocytes. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) cytokines were assessed. Flow cytometry was performed to determine the serological immunological cell counts in absolute terms.

Results

The tetravalent vaccine approach induced cellular and humoral immunological responses, with B- and T-lymphocyte responses peaking mainly after booster vaccinations. In addition, the tetravalent vaccine induced elicited cross-reactive and neutralizing antibodies, Angiotensin-converting enzyme 2 – blocking antibodies (ACE2-blocking antibodies), and cell-mediated responses, including S-targeted CD4+ T (helper T) lymphocytes.

The tetravalent vaccine could induce ACE2 blocking and Omicron S binding antibodies without vaccinating with Omicron, indicating broad immune protection against the SARS-CoV-2 variants.

The vaccine also elicited antibodies against the wild-type (WT), Beta, and Delta variants. Ant-S CD4+ T-lymphocyte responses were observed in RM PBMCs, with variable cytokine levels, after 42.0 days of prime vaccination. Albeit, no CD8+ T (cytotoxic T) lymphocyte responses were observed. CD8+ T lymphocyte counts were most elevated following booster vaccination. Elevated CD38, CD69, Ki-67, and HLA-DR expression were observed among T lymphocyte subsets.

Decreased abundance of helper and central cytotoxic memory (CM) T lymphocytes, helper T, and cytotoxic T-naive T lymphocytes were observed following prime vaccination and booster vaccination.

On the contrary, helper and cytotoxic effector memory (EM) T lymphocyte abundance increased following prime-boost vaccination. The findings indicated that the vaccine candidate shifted toward an EM phenotype from a CM phenotype, which might aid in developing robust and rapid vaccination responses.

Conclusion

The study findings showed that the tetravalent vaccine approach conferred broad immune protection against several SARS-CoV-2 variants. The findings could inform vaccine development to reduce the global health burden of COVID-19.

*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.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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