An international team of researchers has provided further evidence to confirm the immunogenicity and efficacy of a recombinant adenovirus vaccine currently being tested in phase 3 trials for its ability to protect against infection with severe acute respiratory coronavirus 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 SARS-CoV-2 spike 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 levels of neutralizing antibodies and reduced infectious viral load in the upper respiratory tract.
Furthermore, a low dose of the vaccine that induced sub-optimal, non-protective responses did not exacerbate respiratory disease in animals that already had breakthrough infection. Frank Wegmann from Janssen Vaccines & Prevention B.V. in The Netherlands and colleagues say this addresses the concert that coronavirus vaccines inducing suboptimal immunity could predispose to vaccine-associated enhanced respiratory disease (VAERD).
The team says that overall, these preclinical data confirm the efficacy of the 1-dose vaccine regimen, demonstrate the added benefit of a second dose and show no signs of a risk for VAERD under conditions of suboptimal immunity.
A pre-print version of the paper is available on the bioRxiv* server while the article undergoes peer review.
Previous studies of the vaccine demonstrated efficacy
The researchers previously demonstrated that a single dose of the (Ad26) vaccine expressing stabilized SARS-CoV-2 spike (Ad26.COV2.S) was immunogenic in animals and protected non-human primates against challenge with SARS-CoV-2.
They also showed that the vaccine protected Syrian hamsters with infection characterized by severe clinical disease following high-dose intranasal challenge. In this animal model, a challenge was performed using the SARS CoV-2 strain USA-WA1/2020, which expresses a spike sequence that is 100% homologous to the Ad26.COV2.S vaccine antigen.
However, a SARS-CoV-2 variant with a D614G spike substitution has since become the most prevalent strain. Furthermore, new strains with additional spike mutations are also emerging and becoming more widespread.
“This mutation [D614G] has been associated with increased viral fitness and enhanced infectivity and has now become the dominant variant in large parts of the world, although likely to be replaced over time by new variants that are constantly emerging,” writes Wegmann and the team.
What did the researchers do?
The team investigated the immunogenicity and protective efficacy induced by the Ad26.COV2.S vaccine in a Syrian hamster model of moderate disease following challenge with a SARS-CoV-2 strain containing the currently most prevalent G614 spike variant.
Immunization with either 109 or 1010 particles of Ad26.COV2.S induced substantial neutralizing antibody titers and completely protected more than 80% of animals inoculated with SARS-CoV-2 from developing lung infection and pneumonia, but not upper respiratory tract infection.
Vaccination reduced viral replication in the lungs by 6 log10 below the level observed among control animals. Many hamsters that received the higher dose showed undetectable viral replication.
A second vaccine dose given 4 weeks later boosted neutralizing antibody titers further, which was associated with decreased infectious viral load in the upper respiratory tract.
“Our published data, in combination with our present study, indicate that Ad26.COV2.S-elicited immune responses give adequate protection against SARS-CoV-2 variants with and without the D614G spike substitution,” say the researchers.
What about VAERD?
A potential concern surrounding coronavirus vaccines is that they may predispose to disease enhancement following breakthrough infection by inducing only low- or non-neutralizing antibodies together with a skewed T helper 2 (TH2) cellular response.
The researchers say that VAERD has been reported for vaccine candidates against SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) in some animal models. However, no evidence of VAERD in studies of SARS-CoV-2 vaccines has been reported to date.
The Ad26 vaccine vector is currently being used in multiple candidate vaccine programs and has so far uniformly induced neutralizing antibodies and cellular immune responses with a skewed Th1 cellular response in non-clinical and clinical studies.
“However, additional animal studies at suboptimal immunity to allow breakthrough infection are considered important to address the potential risk of predisposition for VAERD by Ad26.COV2.S.,” they write.
Testing for VAERD
The team assessed the potential for predisposition to VAERD by immunizing the hamsters with doses of Ad26.COV2.S doses that induced antibody levels too low to prevent viral replication in the lung.
The lower respiratory tract histopathology scores of animals with breakthrough infection that subsequently had suboptimal immune responses did not show any signs of VAERD, compared with animals in the control group.
“These results imply that the theoretical risk that Ad26.COV2.S would predispose for VAERD is minimal,” says the team.
The vaccine should 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 SARS-CoV-2 G614 spike variant virus.
“The excellent potency of Ad26.COV2.S and the absence of data that it would predispose for VAERD, supports its continuous evaluation in the ongoing Phase 3 clinical trials in a single and a two-dose regimen (NCT04505722 and NCT04614948, respectively),” they conclude.
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.