In a recent preprint* uploaded to the bioRxiv server, researchers in the United States developed and tested a novel mucosal-administered adenoviral-vector vaccine christened "ChAd-SARS-CoV-2-S" against XBB.1.16, a heterologous Omicron strain. Their findings in nonhuman primates revealed that unlikely conventional anti-Omicron vaccines, which lose efficacy over time, ChAd provided durable and effective immunity against the virus. This study suggests ChAd and other vaccines delivered by mucosal-delivery virus-vectored vaccines may be the way forward in humanity's continued efforts against the coronavirus disease 2019 (COVID-19) pandemic.
Study: Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates. Image Credit: DALL·E 3
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Global Health Threat of COVID-19 and Vaccine Limitations
The World Health Organization (WHO) has estimated over 771 million infections and almost 7 million mortalities since the start of the coronavirus disease 2019 (COVID-19) pandemic in late 2019, making it one of the worst in recorded history. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) family, which, like all coronaviruses, intrinsically evolves at a fast rate. Currently, at least five strains and thousands of substrains of the virus exist.
The most severe and virulent stain is the Omicron lineage. First discovered in South Africa in November 2021, the virus rapidly spread globally and outcompeted other COVID-19 strains, remaining the currently dominant COVID-19 lineage worldwide. While the development and widespread delivery of messenger RNA (mRNA) based intramuscularly (IM)-delivered vaccines against the virus has substantially reduced its spread and mortality in humans, recent research has revealed that vaccine-derived immunity is waning.
A combination of rapid viral evolution and the low half-life of conventional vaccine-primed immune cells necessitates novel anti-Omicron interventions, lest we expose ourselves to the resurgence of COVID-19 and another wave of the pandemic.
Exploring Mucosal Immunization Against COVID-19
In the present study, researchers evaluated the efficacy of a novel mucosal-administered vaccine that they previously developed in nonhuman primates infected with XBB.1.16, a heterologous Omicron strain. The study cohort comprised 2- to 6-month-old Indian-origin rhesus macaques (Macaca mulatta) which had been administered mRNA vaccines five months prior via two IM injection doses, four weeks apart. Twenty macaques were divided into age- and sex-matched case (ChAd) and control (only IM vaccine) cohorts.
Eight macaques received an IM booster dose, and six macaques received an intra-nasal (IN) booster dose 32 weeks following initial vaccine priming. Six received the current study treatment (ChAd) as a booster, and four received only the ChAd vaccine without any mRNA vaccine priming.
ChAd Vaccine Development and Delivery
The novel vaccine named "ChAd-SARS-CoV-2" was synthetically in vitro using a combination of SARS-CoV-2 spike (S) proteins S-2P derived from monovalent Wuhan-1 and bivalent Wuhan-1/BA.5 COVID strains. The sequence was incorporated into a vector called ChAd-SARS-CoV-2 -BA.5-S, a replication-incompetent simian vector derived from Ad36. The vectors were used to infect HEK-293 cells and expressed proteins were purified using Cesium chloride (CsCL) density-gradient ultracentrifugation, a method used for separating molecules with slight differences in density.
Once viral particle concentrations were confirmed using spectrophotometry, a pediatric silicone face mask was used to deliver the treatment (vaccine for cases, placebo for controls) directly into the lungs of each macaque cohort. Additionally, mucosal delivery involving intra-nasal sprays of diluted treatments (ChAd vaccine or placebo) was administered.
Methodology for Vaccine Efficacy Evaluation
The challenge virus used in this study was the XBB.1.16 (EPI_ISL_17417328) Omicron variant, propagated in VeroE6-TMPRSS2 cells. For evaluations of viral binding following macaque infection, serum- and mucosal binding and ACE2-S binding inhibition assays were used. Viral infectivity was estimated using a TCID50 quantification assay, and vaccine efficacy using an automated SARS-CoV-2 lentiviral pseudotyped neutralization assay.
Kruskal-Wallis tests were used for statistical analyses of results from the three study cohorts – Conventional vaccine alone, conventional vaccine + ChAd booster, and ChAd vaccine alone.
Key Findings from the ChAd Vaccine Study
The primary findings from this study were: 1. Tissue-specific viral load depended upon the delivery route. The conventional IM delivery route was found to elicit viral immunity in only the nose, while the IN delivery route elicited immunity in both the nasal mucosa and the lungs. This is important, as previous research has shown that COVID-19 viruses concentrate their activity and replication in both nasal and lung tissue before spreading to the rest of the somatic cells and restricting them to these tissues could result in significantly improved disease outcomes.
Second, IM vaccines were found to primarily boost Immunoglobulin G (IgG) antibodies, while mucosal vaccines like ChAd were found to upregulate both IgG and IgA. IgA antibodies have a significantly longer half-life than IgG, thereby contributing to durable and extended immunity against COVID-19. Thirdly, while the immediate efficacy of conventional IM vaccines displayed a rapid peak followed by gradual decay (over two months), ChAd remained relatively stable over five months.
"These data indicate that vaccines directed at both the lungs and nose (AE groups) can induce broad multi-compartment mucosal immunity, which effectively and rapidly suppresses virus replication in both the upper and lower respiratory tract such that insufficient antigen is available to promote systemic recall responses and would be consistent with preventing infection. However, mucosal vaccination directed primarily at the nose (IN boost group), while capable of boosting upper airway IgA titers and preventing local virus replication, did not suppress virus replication in the lungs as effectively as the AE boost.
Implications for Future Pandemic Response
In the present study, researchers developed and tested the efficacy and persistent immunity of a novel ChAd vaccine against nonhuman primates (NHP) infected with an Omicron COVID-19 strain. Unlike IM delivery used in conventional vaccines, the novel vaccine followed an IN delivery route. Findings revealed that the novel vaccine provided stable and durable protection against Omicron for five months or more, compared to the conventional vaccines, which lost efficacy in two months or less.
"…this study provides a proof-of-principle for mucosal vaccination in a relevant pre-clinical model to achieve broad and durable cross-variant humoral and cellular immunity with functional prevention of XBB.1.16 infection."
*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.
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