Mucosal COVID vaccine candidate with strong protection in macaques

A recent research paper published on the bioRxiv* The preprint server illustrated the protective efficacy of the potential intranasal pediatric parainfluenza virus vector coronavirus disease 2019 (COVID-19) vaccine, B/HPIV3/S-6P, in macaques.

Study: Intranasal Pediatric Parainfluenza Virus Vector SARS-CoV-2 Vaccine Candidate Protects Macaques. ​​​​​​​Image credit: NIAID

background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect people of all ages. Although COVID-19 is often mild in young children compared to adults, thousands of children in the United States (US) have been hospitalized for SARS-CoV-2 infection, with about a third of them having no prior medical problems . Over 800 US children ages 0-11 have died from COVID-19, and during the US Fall/Winter 2021/2022 SARS-CoV-2 outbreak, children accounted for more than 25% of the COVID-19 cases out. In addition, COVID-19 rarely leads to multisystemic inflammatory disease (MIS-C) in children.

While SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccines are available for children five years and older, no vaccine has been approved or recommended for children under the age of five. Furthermore, the disadvantage of the current SARS-CoV-2 mRNA and other parenteral vaccines is that they did not directly induce immunity in the airways, where SARS-CoV-2 replication, entry, exit and disease mainly occur. Therefore, pediatric COVID-19 vaccines that confer systemic and mucosal immunity are needed.

About the study

In the present work, scientists developed B/HPIV3/S-6P, a live attenuated chimeric bovine/human parainfluenza virus type-3 (B/HPIV3)-vectorized COVID-19 vaccine option harboring prefusion-stabilized SARS-CoV-2 Spike (S )-Protein. Interestingly, the B/HPIV3 vector was originally developed as a pediatric vaccine trial against a negative single-stranded RNA virus, HPIV3, a major cause of respiratory disease, particularly in babies and young children under the age of five.

The authors of the present research have recently shown that B/HPIV3 containing perfusion-stabilized SARS-CoV-2 S-protein effectively protects hamsters from infection with a SARS-CoV-2 isolate matched to a vaccine antigen , and pneumonia, weight loss and effective reduction prevents SARS-CoV-2 replication in the lower and upper airways.

In this study, the team tested the immunogenicity, safety and protective capacity of a single dose of intratracheal/intranasal (IT/IN) B/HPIV3/S-6P vaccination in rhesus monkeys (RMs). They determined SARS-CoV-2-S-specific T-cell, systemic, and mucosal antibody responses to assess immunogenicity. In addition, they analyzed the neutralizing antibody responses of B/HPIV3/S-6P to the vaccine-matched SARS-CoV-2 strain and the SARS-CoV-2 Omicron BA.1, Delta, Beta and Alpha variants (VOCs) . ) in vaccinated RMs. The team also evaluated the protective ability of B/HPIV3/S-6P against the SARS-CoV-2 challenge before advancing B/HPIV3/S-6P into a Phase I clinical trial.

Results and Conclusions

According to the study results, B/HPIV3/S-6P and B/HPIV3 did not affect the overall health of RMs after vaccination, showing that the expressed SARS-CoV-2 S protein and this vector is safe in this non-human organism were primate species. A single intratracheal/intranasal B/HPIV3/S-6P vaccine dose elicited robust SARS-CoV-2 S-specific mucosal immunoglobulin G (IgG) and IgA responses in the airways. Vaccination also induced high SARS-CoV-2 receptor binding domains (RBD) and S-specific antibody titers (IgA, IgM and IgG) in serum, effectively neutralizing SARS-CoV-2 VOCs. Anti-RBD and anti-S-IgG responses were consistent with those found in human convalescent plasma with high anti-RBD and anti-S-IgG antibody titers.

Intranasal/intratracheal immunization with B/HPIV3/S-6P induces mucosal antibody responses to SARS-CoV-2 S in the upper and lower airways. Rhesus monkeys (n=4 per group) were immunized intranasally/intratracheally with B/HPIV3/S-6P or B/HPIV3 (control) (Figure S1). To determine the mucosal antibody response in the upper airways, nasal washes (NW) were performed before immunization and on days 14, 21, and 28. To analyze the antibody response in the lower airways, bronchoalveolar lavages (BAL) were collected before immunization and on days 9, 21 and 28 pi. (A and B) S- and receptor-binding domain (RBD)-specific mucosal IgA and IgG titers on the indicated days after immunization (pi) in the upper (A) and lower (B) airways, determined by time-resolved dissociation-enhanced lanthanide fluorescence (DELFIA- TRF) immunoassay. Endpoint titers are expressed in the protocol₁₀ for mucosal IgA and IgG to a secreted prefusion-stabilized form (aa 1-1208; S-2P) of S protein (left panels) or to a fragment of S protein (aa 328-531) containing SARS-CoV-2 RBD (right panels). The detection limit is 1.6 log₁₀ (dotted line). B/HPIV3/S-6P immunized RMs are shown in blue while B/HPIV3 immunized RMs are green, with each RM represented by a symbol. *P<0.05 (Two Way ANOVA, Sidak multiple comparison test).

The vaccine-matched SARS-CoV-2 WA1/2020 isolate and alpha and delta VOCs were efficiently neutralized by serum antibodies. Nonetheless, these sera had minimal neutralizing activity against beta and omicron VOCs. This conclusion indicated that similar to any SARS-CoV-2 vaccination, a booster dose of B/HPIV3/S-6P may be required to increase antibody levels and affinity maturation, allowing for broader antigen identification and immunity to VOCs.

B/HPIV3/S-6P vaccination likely produced long-lived antigen-selective tissue-resident T and B cells in the mucosa, although this has not been confirmed. B/HPIV3/S-6P elicited strong pulmonary and systemic S-specific CD8+ and CD4+ T cell responses, which are composed of memory cells resident in lung tissue.

SARS-CoV-2 replication in lung tissue and airways of vaccinated macaques was undetectable after viral challenge. RMs were fully protected against the SARS-CoV-2 challenge one month after vaccination. Under the present experimental circumstances, no proliferation of SARS-CoV-2 challenge virus was detected in the airways or lung tissues of vaccinated RMs, suggesting sterilizing immunity. On the other hand, the durability of the protection was still unknown and will be investigated in a follow-up study. After challenge, the authors found a memory reflex of S-specific CD4+ T cells from B/HPIV3/S-6P-vaccinated RMs in the blood but not in the lower airways.

Taken together, the study results showed that a single topical B/HPIV3/S-6P vaccination in rhesus monkeys was significantly protective and immunogenic against COVID-19. Current data encourage the development of this vaccine candidate as a single vaccine or in a prime/boost mix with existing SARS-CoV-2 neonatal and infant vaccines. According to the authors, a phase I study with B/HPIV3/S-6P is also being conducted.

*Important NOTE

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