Study supports continuation of phase 3 trials of Ad26.COV2.S SARS-CoV-2 vaccine

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

The vaccine comprises a recombinant adenovirus serotype 26 (Ad26) vaccine vector expressing a stabilized form of the advanced SARS-CoV-2 antigen that the virus uses to bind to and enter host cells.

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

A second dose further increased the levels of neutralizing antibodies and reduced the infectious viral load in the upper respiratory tract.

Furthermore, a low dose of the vaccine which induced suboptimal and non-protective responses did not exacerbate respiratory disease in animals which already had rupture infection. Frank Wegmann of Janssen Vaccines & Prevention BV in the Netherlands and colleagues say this relates to the gig that coronavirus vaccines inducing suboptimal immunity may predispose to vaccine-associated enhanced respiratory disease (VAERD).

The team states that overall, these preclinical data confirm the effectiveness of the 1-dose vaccine regimen, demonstrate the additional benefit of a second dose, and show no signs of risk of VAERD under conditions of sub-immunity. optimal.

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

Previous studies of the vaccine have shown its effectiveness

Researchers have previously shown that a single dose of the vaccine (Ad26) expressing the stabilized SARS-CoV-2 peak (Ad26.COV2.S) was immunogenic in animals and protected non-human primates against SARS-challenge. CoV-2.

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

However, a SARS-CoV-2 variant with a D614G spike substitution has since become the most prevalent strain. In addition, new strains with additional tip mutations are also emerging and spreading.

“This mutation [D614G] has been associated with improved viral fitness and increased infectivity and has now become the dominant variant in large parts of the world, although it is likely to be replaced over time by new variants which are constantly emerging ”, writes Wegmann and the team.

What did the researchers do?

The team studied the immunogenicity and protective efficacy induced by the Ad26.COV2.S vaccine in a Syrian hamster model of moderate disease following challenge with a strain of SARS-CoV-2 containing the peak variant G614 currently the most widespread.

Immunization with either 10⁹ or 10^ten Ad26.COV2.S particles induced substantial neutralizing antibody titers and completely protected over 80% of animals inoculated with SARS-CoV-2 from the development of lung infection and pneumonia, but no upper respiratory tract infection.

Vaccination reduced viral replication in the lungs by 6 log_ten lower than the level observed in control animals. Many hamsters that received the highest dose showed undetectable viral replication.

A second dose of vaccine given 4 weeks later further increased the titers of neutralizing antibodies, which was associated with a decrease in the infectious viral load in the upper respiratory tract.

“Our published data, in combination with our current study, indicate that the immune responses induced by Ad26.COV2.S offer adequate protection against the SARS-CoV-2 variants with and without the peak substitution D614G,” the researchers explain. .

And the VAERD?

A potential concern surrounding coronavirus vaccines is that they may predispose to increased disease after breakthrough infection by inducing only weakly or non-neutralizing antibodies with an asymmetric T helper 2 (TH2) cell response.

Researchers say VAERD has been reported for candidate vaccines against SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) in some animal models. However, no evidence of VAERD in SARS-CoV-2 vaccine studies has been reported to date.

The Ad26 vaccine vector is currently used in several candidate vaccine programs and has so far consistently induced neutralizing antibodies and cellular immune responses with an asymmetric Th1 cellular response in non-clinical and clinical studies.

“However, additional studies in animals with suboptimal immunity to allow for breakthrough infection are considered important to address the potential risk of predisposition to VAERD by Ad26.COV2.S.,” they write.

VAERD test

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

Lower respiratory tract histopathologic scores of animals with rupture infection that subsequently had suboptimal immune responses showed no evidence of VAERD, compared to animals in the control group.

“These results imply that the theoretical risk that Ad26.COV2.S predisposes to VAERD is minimal,” the team explains.

Vaccine to continue to be evaluated in ongoing Phase 3 trials

The researchers say the study confirms that the Ad26.COV2.S vaccine is highly immunogenic and can protect hamsters against challenge with a peak variant SARS-CoV-2 G614 virus.

“The excellent potency of Ad26.COV2.S and the absence of predisposing data to VAERD, supports its continued evaluation in ongoing phase 3 clinical trials in one and two doses (NCT04505722 and NCT04614948, respectively),” Conclude -they.

*Important Notice

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