Correction: Modification of Ad5 Hexon Hypervariable Regions Circumvents Pre-Existing Ad5 Neutralizing Antibodies and Induces Protective Immune Responses

Abstract

The development of an effective malaria vaccine is a high global health priority. Vaccine vectors based on adenovirus type 5 are capable of generating robust and protective T cell and antibody responses in animal models and are currently being evaluated in clinical trials for HIV and malaria. They appear to be more effective in terms of inducing antigen-specific immune responses as compared with non-Ad5 serotype vectors. However, the high prevalence of neutralizing antibodies to Ad5 in the human population, particularly in the developing world, has the potential to limit the effectiveness of Ad5-based vaccines. We have generated novel Ad5-based vectors that precisely replace the hexon hypervariable regions with those derived from Ad43, a subgroup D serotype with low prevalence of neutralizing antibody in humans. We have demonstrated that these hexon-modified adenovectors are not neutralized efficiently by Ad5 neutralizing antibodies in vitro using sera from mice, rabbits and human volunteers. We have also generated hexon-modified adenovectors that express a rodent malaria parasite antigen, PyCSP, and demonstrated that they are as immunogenic as an unmodified vector. Furthermore, in contrast to the unmodified vector, the hexon-modified adenovectors induced robust T cell responses in mice with high levels of Ad5 neutralizing antibody. We also show that the hexon-modified vector can be combined with unmodified Ad5 vector in prime-boost regimens to induce protective responses in mice. Our data establish that these hexon-modified vectors are highly immunogenic even in the presence of pre-existing anti-adenovirus antibodies. These hexon-modified adenovectors may have advantages in sub-Saharan Africa where there is a high prevalence of Ad5 neutralizing antibody in the population.

Adenovirus with DNA Packaging Gene Mutations Increased Virus Release

“…Each facet of the Ad capsid contains twelve hexon trimers with hexon pentamers positioned at each vertex of the icosahedral capsid [70,71]. in vivo, hexon is highly immunogenic [72] and contains many hypervariable regions (HVRs) which can be bound by antibodies to neutralize the infectivity of Ads [73]. Hexon is known to contain nine HVRs located in the DE1 and FG1 loops between the coded 126 and 461 amino acids [73].…”

“…in vivo, hexon is highly immunogenic [72] and contains many hypervariable regions (HVRs) which can be bound by antibodies to neutralize the infectivity of Ads [73]. Hexon is known to contain nine HVRs located in the DE1 and FG1 loops between the coded 126 and 461 amino acids [73]. The mutations located at 20378 and 21630 are not contained within one of these nine HVRs.…”

High-Throughput Screening for the Prevalence of Neutralizing Antibodies against Human Adenovirus Serotype 5

“…We also confirmed HAdV-C5 neutralization in the sera of rabbits, horses, cats, and dogs, showing the broad importance of prescreening for neutralization in multiple species. Indeed, previous research into both gene therapy and vaccinology has utilized all these species [ 29 , 44 , 45 ]. Future biomedical research in these species should be preceded by screening potential animals for HAdV-C5-neutralizing antibody responses.…”

“…While several HAdV-C5 neutralization assays have been developed in the past, they usually use single reporter readouts, have limited dynamic ranges, or are unsuitable for high-throughput studies [ 26 , 27 , 28 , 29 ]. Additionally, most of these assays are labor-intensive, expensive, and time-consuming, leading to variable results.…”