Study supports ongoing phase 3 testing of the Ad26.COV2.S SARS-CoV-2 vaccine

An international team of researchers has provided further evidence to validate the immunogenicity and efficacy of a recurrent adenovirus vaccine currently being tested in phase 3 trials for its ability to protect against infection with true respiratory coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus infection 2019 (COVID-19).

The vaccine contains a serotype 26 (Ad26) adenovirus vaccine vector that expresses a stable form of the SARS-CoV-2 spike antigen that the virus uses to bind and enter host cells.

In a hamster model of moderate disease, an initial dose of the vaccine induced major titers of antibodies and completely protected most animals from lung infection and pneumonia after challenge with SARS-CoV- 2.

With a second dose, increased levels of neutral antibodies increased and decreased infectious viral behavior in the upper respiratory tract.

Moreover, low doses of the vaccine did not induce subcutaneous, non-immune responses in respiratory disease in animals that already had an infectious disease. Frank Wegmann of Janssen Vaccines & Prevention BV in the Netherlands and colleagues say this addresses the hypothesis that coronavirus vaccines that cause suboptimal immunity may be susceptible to vaccine-associated respiratory disease ( VAERD).

The team says that, overall, these preclinical data confirm the effectiveness of the 1-dose vaccine regimen, show an additional benefit of a second dose and show no signs of risk for VAERD under suboptimal immune conditions.

A pre-printed version of the paper is available on the bioRxiv * server while the article is under peer review.

Previous studies on the vaccine have shown efficacy

The previous researchers showed that a single dose of the vaccine (Ad26) induced a sustained immunogenic SARS-CoV-2 spike (Ad26.COV2.S) in animals and protected non-human primates against challenge. the SARS-CoV-2.

They also showed that the vaccine protected Syrian hamsters with a disease characterized by severe clinical infection following a high-dose intranasal challenge. In this animal model, a challenge was achieved using the SARS CoV-2 USA-WA1 / 2020 strain, which exerts a spike sequence that is 100% homologous to the vaccine antigen Ad26.COV2.S.

However, SARS-CoV-2 differentiation with D614G spike substitution is now the most common type. In addition, new series with additional spike mutations appear and become more diffuse.

“This reversal [D614G] it has been associated with increased viral susceptibility and improved infectivity and has now become a major variant in large parts of the world, although new changes are likely to be introduced. place over time, ”wrote Wegmann and team.

What did the researchers do?

The team investigated the immunogenicity and immune efficacy induced by the Ad26.COV2.S vaccine in a Syrian hamster model of moderate infection after challenge with a SARS-CoV-2 strain containing the most common G614 spike variant. -currently.

One – part vaccine 10⁹ no 10¹⁰ fragments of Ad26.COV2.S titers caused major neutralizing antibody and completely protected more than 80% of animals with SARS-CoV-2 from developing lung disease and pneumonia, but not respiratory tract disease. high.

Vaccine reduced viral replication in the lungs by 6 logs₁₀ below the level observed among control animals. Many hamsters that received the higher dose showed unstable viral reproduction.

A second dose of vaccine administered 4 weeks later further induced antibody titers, which were associated with a decrease in infectious viral load in the upper respiratory tract.

“Our published data, in conjunction with our current study, indicates that immune responses obtained from Ad26.COV2.S provide adequate protection against SARS-CoV modifications. -2 with and without D614G spike replacement, ”the researchers say.

What about VAERD?

A potential concern about coronavirus vaccines is that they could lead to an increase in disease after infection with the ingestion of only low- or neutral antibodies combined with a person’s T-cellular response (2 2). -help.

The researchers report that VAERD has been reported for candidates for vaccination against SARS-CoV-1 and Middle Eastern respiratory syndrome coronavirus (MERS-CoV) in some animal models. However, to date no evidence of VAERD has been reported in studies of SARS-CoV-2 vaccines.

The Ad26 vaccine vector is currently used in multivariate immunization programs and to date has provided neutral stimulation of antibodies and cellular immune responses with a sparse Th1 cellular response in nonclinical and clinical studies .

“However, additional animal studies at suboptimal immunity to rule out invasion disease are considered important to address the potential risk for VAERD with Ad26.COV2.S.,” they write.

Tests for VAERD

The team assessed the potential for predisposition to VAERD by vaccinating the hamsters with doses of Ad26.COV2.S doses that stimulated antibody levels too low to prevent viral replication in the lung.

Histopathology scores did not show the lower respiratory tract of animals with fracture disease that subsequently received suboptimal immune responses showed no signs of VAERD, compared with animals in the control group.

“These results mean that the theoretical risk predicted by Ad26.COV2.S for VAERD is very small,” the team said.

Evaluation of the vaccine should be continued in ongoing Phase 3 trials

The researchers say the study confirms that the Ad26.COV2.S vaccine is highly protective and can protect hamsters from exposure to the SARS-CoV-2 G614 variant spike virus.

“The strong potency of Ad26.COV2.S and in the absence of data it would predict for VAERD, supports continuous evaluation in Phase 3 single-dose and double-dose clinical trials (NCT04505722 and NCT04614948, respectively), ”They conclude.

* Important message

bioRxiv publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or be treated as information established.