Mucosal vaccine shows lasting defense against SARS-CoV-2 Omicron in primate study

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Uploaded in recent preprint* bioRxiv Researchers from Server, USA developed and tested a novel mucosal-administered adenoviral-vector vaccine called “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, confer durable and effective immunity against ChAd virus. This study suggests that ChAd and other vaccines delivered by mucosal-delivered virus-vectored vaccines may be the way forward for humanity’s continued efforts against the coronavirus disease 2019 (COVID-19) pandemic.

Study: mucosal adenoviral-vectored vaccine sustainably prevents XBB.1.16 infection in nonhuman primates.  Image credit: DALL·E 3Study: Mucosal adenoviral-vectored vaccine sustainably prevents XBB.1.16 infection in nonhuman primates. Image credit: DALL·E 3

*Important Notice: bioRxiv Preliminary scientific reports are published that are not peer-reviewed and, therefore, should not be considered conclusive, guidelines for clinical practice/health-related behavior, or established information.

The global health threat of COVID-19 and vaccine limitations

The World Health Organization (WHO) has estimated more than 771 million infections and nearly 7 million deaths 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, evolves rapidly internally. Currently, at least five strains and thousands of substrains of the virus exist.

The most serious and deadly scar is the Omicron lineage. First discovered in South Africa in November 2021, the virus quickly spread globally and outcompeted other COVID-19 strains, remaining the dominant global COVID-19 lineage today. While the development and widespread delivery of messenger RNA (mRNA)-based intramuscular (IM) vaccines against the virus have significantly reduced its prevalence and mortality in humans, recent studies have revealed that vaccine-derived immunity is waning.

The combination of rapid viral evolution and the short half-life of conventional vaccine-primed immune cells necessitates novel anti-Omicron interventions, lest we expose ourselves to a resurgence of Covid-19 and another wave of pandemics.

Exploring mucosal immunization against COVID-19

In the current study, the researchers evaluated the efficacy of a novel mucosal-administered vaccine they had previously developed in nonhuman primates infected with XBB.1.16, a heterologous Omicron strain. The study group consisted of 2- to 6-month-old Indian-origin rhesus macaques (Makaka Multa) that administered the mRNA vaccine five months earlier with two IM injection doses four weeks apart. Twenty macaques were divided into age- and sex-matched case (ChAd) and control (IM vaccine only) groups.

Eight macaques received an IM booster dose, and six macaques received an intra-nasal (IN) booster dose 32 weeks after primary 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” synthetically uses a combination of the SARS-CoV-2 spike (S) protein S-2P to construct a strain sequence derived from a synthetic Wuhan-1 and bivalent Wuhan-1/BA.5 Covid-19 strain. SARS-CoV-2 was subcloned into a vector called -BA.5-S, a replication-incompetent simian vector derived from Ad36. The vectors were used to infect HEK-293 cells and the expressed proteins were purified using cesium chloride (CsCL) concentration-gradient ultracentrifugation, a method used to separate molecules with slight differences in concentration.

Once viral particle concentrations were confirmed using spectrophotometry, a pediatric silicone face mask was used to deliver treatment (vaccine for cases, placebo for controls) directly into the lungs of each macaque cohort. In addition, mucosal delivery involved intra-nasal spray of the combination treatment (ChAd vaccine or placebo).

Methods for Evaluating Vaccine Efficacy

The challenge virus used in this study was XBB.1.16 (EPI_ISL_17417328) Omicron variant, propagated in VeroE6-TMPRSS2 cells. For assessment of viral binding after macaque infection, serum- and mucosal binding and ACE2-S binding inhibition assays were used. Viral infectivity was estimated using a TCID50 Quantitative testing and vaccine efficacy using an automated SARS-CoV-2 lentiviral pseudotyped neutralization assay.

Kruskal-Wallis tests were used for statistical analysis of the results of the three study groups—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 depends on the route of delivery. The conventional IM delivery route was found to elicit viral immunity only in the nose, while the IN delivery route induced immunity in both the nasal mucosa and lungs. This is important, as previous studies have shown that focusing the activity and replication of the COVID-19 virus in both nasal and lung tissues before spreading to the rest of the somatic cells and restricting them to these tissues can significantly improve disease outcomes.

Second, IM vaccines have been found to primarily increase immunoglobulin G (IgG) antibodies, whereas mucosal vaccines such as ChAd have been found to upregulate both IgG and IgA. IgA antibodies have a significantly longer half-life than IgG, thus contributing to sustained and enhanced immunity against COVID-19. Third, while the immediate efficacy of conventional IM vaccines exhibits a rapid peak followed by a gradual decay (over two months), ChAd was relatively stable over five months.

“These data indicate that vaccines directed at both the lung and the nose (AE group) can induce broad multi-compartment mucosal immunity, which effectively and rapidly suppresses virus replication in both the upper and lower respiratory tract so that insufficient antigen is available for systemic dissemination. Recall responses and would be consistent with prevention of infection. However, mucosal vaccination directed primarily to the nose (IN boost group), while capable of increasing upper airway IgA titers and preventing local virus replication, did not suppress virus replication in the lung 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 non-human primates (NHP) infected with the Omicron Covid-19 strain. Unlike the IM delivery used in conventional vaccines, the novel vaccine follows an IN delivery route. The findings revealed that the novel vaccine provides stable and durable protection against Omicron for five months or more compared to conventional vaccines, which lose effectiveness 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 resistance to XBB.1.16 infection.”

*Important Notice: bioRxiv Preliminary scientific reports are published that are not peer-reviewed and, therefore, should not be considered conclusive, guidelines for clinical practice/health-related behavior, or established information.

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