Virus-like particles containing spikes induce strong sterile immunity to macaque SARS-CoV-2

A team of international scientists recently coated the liposomes with a synthetic spike (S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus. We have developed a virus-like particle (VLP). Illness 2019 (COVID-19).In non-human primates, VLPs containing S are highly immunogenic Neutralizing antibody Titer and T helper type 1 CD4 + biased T cell response.

study: Immunization with synthetic SARS-CoV-2S glycoprotein virus-like particles protects macaques from infection..

Background

SARS-CoV-2 is an enveloped ribonucleic acid (RNA) virus containing S. Glycoprotein On its surface to help invade the host cell. Since the S protein is the most immunogenic viral component of SARS-CoV-2, it is also a major target for most therapeutic monoclonal antibody therapies and vaccines. Importantly, enrichment of S-target antibodies has been observed in individuals who have recovered with COVID-19.

In the current study bioRxiv* Scientists, a preprint server, developed VLPs by coating liposomes with synthetic S trimers and tested their antiviral effects in cynomolgus monkeys. Cynomolgus monkeys are an established non-human primate model often used to study innate and adaptive immune responses during infection or vaccination.

Development of VLPs including spikes

Scientists have generated native S trimers by expressing synthetic S protein constructs in mammalian cells and then purifying them by size exclusion chromatography. Given the low thermal stability of S glycoproteins, researchers chemically crosslinked the S trimer with formaldehyde. This preserved the original structure for a long period of time. The crosslinked S trimer was coated on liposomes to produce synthetic S-containing VLPs.

Virus neutralizing effect of VLP including spikes

For safety and immunogenicity profiling studies, scientists intramuscularly administered VLPs containing monophospholipid A adjuvant S to cynomolgus monkeys at weeks 0, 4, 8, and 19. Serum samples were then collected from immune animals to measure immunogenicity responses.

Study 1^NS And 2^NS Immunization significantly increased the titer of anti-receptor binding domain (RBD) -binding antibody, but 3^rd Immunization primarily induced S-specific non-RBD-binding antibodies. However, no further induction of antibody titer was observed after 4 days.^NS Immunity.

(A) Vaccination, challenge and sampling schemes. The syringe indicates the time of vaccination, the red indicates the time of serum collection, and the viral particles indicate the time of challenge. Symbols that identify individual macaques are used in all figures. (B) Elisa of SARS-CoV-2S protein-specific IgG determined during the 0, 2, 4, 6, 8, 11, 12, 19, 22, 24, 25, 28 week study. Four animals are shown. (C) Elisa of SARS-CoV-2FA-S-protein-specific IgG determined during the study. (D) Elisa of SARS-CoV-2 SRBD-specific IgG determined during the study.

Scientists performed a virus neutralization assay using wild type PseudovirusThis revealed that the first three immunizations significantly increased the neutralizing antibody titer in serum.However, as with the bound antibody response, no further boost in neutralization titer was observed after 4.^NS Immunity.

Similar levels of neutralization were observed after 3 times for B.1.1.7, B.1.351, and P1 variants of SARS-CoV-2.^rd Immunization with S-containing VLP. 2^NS Immunization appeared already sufficient to induce protective neutralization, as no further increase in titer was observed after 4.^NS Immunity.

To specifically determine antibody-specific neutralization, scientists ly removed anti-RBD antibodies from immunized serum samples. Interestingly, RBD antibody-depleted sera showed 10-30% neutralization. This highlights the neutralizing potency of non-RBD antibodies and the importance of synergies between RBD-specific and non-specific antibodies to achieve high neutralization effects.

(A) Changes in SARS-CoV-2 neutralizing antibody titers have been shown for sera collected at weeks 0, 2, 4, 6, 8, 11, 12, and 19. The bar shows the median titer of the four animals. B) Serum from week 11 was depleted of RBD-specific antibodies by affinity chromatography, and the neutralization activity of complete sera of each animal was set to 100% and compared with RBD-depleted sera and RBD-specific sera. ..

Therapeutic effect of VLPs including spikes

For further validation, scientists challenged animals intranasally and intratracheally with SARS-CoV-2 5 weeks after the last immunization with S-containing VLPs. As an control, non-immunized animals were also infected with SARS-CoV-2.

Estimates of genomic and subgenome viral RNAs show that, unlike non-immunized animals that showed high viral load in the upper and lower respiratory tracts, all immunized animals were completely protected from infection and viral load in the respiratory tract. Not detected.

Consistent with these findings, no further increase in binding and neutralizing antibody responses was observed in immunized animals after viral challenge. In these animals, a gradual decrease in antibody response was observed from the day of the SARS-CoV-2 challenge to 3 weeks after the challenge.

In contrast, control animals showed peak neutralizing titers 2 weeks after the virus challenge. All immunized animals showed S-specific CD4 + T cell responses prior to virus exposure and remained unchanged 14 days after exposure. However, no detectable S-specific CD8 + T cell response was observed in these animals.

In terms of clinical symptoms, none of the immunized animals showed abnormal lung pathology. In addition, these animals maintained stable levels of monocytes after SARS-CoV-2 infection. Similarly, all control animals showed mild lung lesions and elevated monocyte levels after the challenge.

Importance of research

Current research describes the development of S-containing VLPs that have a significant effect on the induction of sterile immunity against SARS-CoV-2.Importantly, these findings indicate induction of non-RBD antibody after 3^rd Immunization. This may be beneficial in increasing the overall neutralizing effect of the vaccine against mutated viral variants. As scientists have stated, non-RBD antibodies are especially needed to compensate for the loss of RBD-specific neutralization over time.

*Important Notices

medRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.