First-in-Human Randomized Study to Assess the Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus (RSV) Vaccine Based on Chimpanzee-Adenovirus-155 Viral Vector–Expressing RSV Fusion, Nucleocapsid, and Antitermination Viral Proteins in Healthy Adults

Cicconi, Paola; Jones, Claire; Sarkar, Esha; Silva-Reyes, Laura; Klenerman, Paul; Lara, Catherine de; Hutchings, Claire; Moris, Philippe; Janssens, Michel; Fissette, Laurence; Picciolato, Marta; Leach, Amanda; González‐López, Antonio; Dieussaert, Ilse; Snape, Matthew D.

doi:10.1093/cid/ciz653

Cited by 46 publications

(46 citation statements)

References 25 publications

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“…Importantly, we demonstrate here that the vectored vaccine is compatible with the licensed vaccine in a simulated PEP in NHP, since it strongly boosts VNA titers induced by a previous vaccination with RABIPUR. In addition, a homologous boost with ChAd155-RG one year after priming was highly effective in all animals, despite the presence of anti-vector nAb titers similar to those detected in humans with pre-existing cross-reactive immunity to ChAd155 [ 45 ]. On the basis of genetic distance and serological cross-reactivity, the Lyssavirus genus has been subdivided into three broad phylogroups I-III.…”

Section: Discussionmentioning

confidence: 99%

A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

Napolitano¹,

Merone²,

Abbate³

et al. 2020

PLoS Negl Trop Dis

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Rabies, caused by RNA viruses in the Genus Lyssavirus, is the most fatal of all infectious diseases. This neglected zoonosis remains a major public health problem in developing countries, causing the death of an estimated 25,000–159,000 people each year, with more than half of them in children. The high incidence of human rabies in spite of effective vaccines is mainly linked to the lack of compliance with the complicated administration schedule, inadequacies of the community public health system for local administration by the parenteral route and the overall costs of the vaccine. The goal of our work was the development of a simple, affordable and effective vaccine strategy to prevent human rabies virus infection. This next generation vaccine is based on a replication-defective chimpanzee adenovirus vector belonging to group C, ChAd155-RG, which encodes the rabies glycoprotein (G). We demonstrate here that a single dose of this vaccine induces protective efficacy in a murine model of rabies challenge and elicits strong and durable neutralizing antibody responses in vaccinated non-human primates. Importantly, we demonstrate that one dose of a commercial rabies vaccine effectively boosts the neutralizing antibody responses induced by ChAd155-RG in vaccinated monkeys, showing the compatibility of the novel vectored vaccine with the current post-exposure prophylaxis in the event of rabies virus exposure. Finally, we demonstrate that antibodies induced by ChAd155-RG can also neutralize European bat lyssaviruses 1 and 2 (EBLV-1 and EBLV-2) found in bat reservoirs.

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Section: Discussionmentioning

confidence: 99%

A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

Napolitano¹,

Merone²,

Abbate³

et al. 2020

PLoS Negl Trop Dis

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“…Owing to their lower seroprevalence and thus decreased vector neutralization in humans as compared to human Ad5, chimpanzee Ad (ChAd) vectors represent an attractive vaccine platform (3)(4)(5). ChAdvectored candidate vaccines against infectious diseases such as malaria, Ebola, and RSV have shown favorable immunogenicity and tolerability in humans (6)(7)(8)(9)(10)(11). These vaccines drive robust intracellular antigen expression, thus promoting a CD8 + T-cellbiased response, but were also shown to induce antigen-specific CD4 + T-cell responses and antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…These properties have guided the selection of this platform for several vaccine candidates with a ChAd serotype 155 [ChAd155 (12,13)] backbone. These vaccines include the pediatric RSV vaccine ChAd155-RSV (7) currently in Phase II development (NCT02927873), as well as the rabies vaccine ChAd155-RG and the therapeutic hepatitis B vaccine ChAd155-hIi-HBV, both in Phase I development (NCT04019444 and NCT03866187, respectively).…”

Section: Introductionmentioning

confidence: 99%

Innate Immune Responses to Chimpanzee Adenovirus Vector 155 Vaccination in Mice and Monkeys

Collignon¹,

Bol²,

Chalon³

et al. 2020

Front. Immunol.

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Replication-deficient chimpanzee adenovirus (ChAd) vectors represent an attractive vaccine platform and are thus employed as vaccine candidates against several infectious diseases. Since inducing effective immunity depends on the interplay between innate and adaptive immunity, a deeper understanding of innate immune responses elicited by intramuscularly injected ChAd vectors in tissues can advance the platform’s development. Using different candidate vaccines based on the Group C ChAd type 155 (ChAd155) vector, we characterized early immune responses in injected muscles and draining lymph nodes (dLNs) from mice, and complemented these analyses by evaluating cytokine responses and gene expression patterns in peripheral blood from ChAd155-injected macaques. In mice, vector DNA levels gradually decreased post-immunization, but local transgene mRNA expression exhibited two transient peaks [at 6 h and Day (D)5], which were most obvious in dLNs. This dynamic pattern was mirrored by the innate responses in tissues, which developed as early as 1–3 h (cytokines/chemokines) or D1 (immune cells) post-vaccination. They were characterized by a CCL2- and CXCL9/10-dominated chemokine profile, peaking at 6 h (with CXCL10/CCL2 signals also detectable in serum) and D7, and clear immune-cell infiltration peaks at D1/D2 and D6/D7. Experiments with a green fluorescent protein-expressing ChAd155 vector revealed infiltrating hematopoietic cell subsets at the injection site. Cell infiltrates comprised mostly monocytes in muscles, and NK cells, T cells, dendritic cells, monocytes, and B cells in dLNs. Similar bimodal dynamics were observed in whole-blood gene signatures in macaques: most of the 17 enriched immune/innate signaling pathways were significantly upregulated at D1 and D7 and downregulated at D3, and clustering analysis revealed stronger similarities between D1 and D7 signatures versus the D3 signature. Serum cytokine responses (CXCL10, IL1Ra, and low-level IFN-α) in macaques were predominantly observed at D1. Altogether, the early immune responses exhibited bimodal kinetics with transient peaks at D1/D2 and D6/D7, mostly with an IFN-associated signature, and these features were remarkably consistent across most analyzed parameters in murine tissues and macaque blood. These compelling observations reveal a novel aspect of the dynamics of innate immunity induced by ChAd155-vectored vaccines, and contribute to ongoing research to better understand how adenovectors can promote vaccine-induced immunity.

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“…Sequencing of viral samples suggested that modifications were generated post-vaccination in a number of subjects that promoted a reduction in the expression of the F protein correlating with lower neutralizing antibodies in those individuals ( 27 ). A recently developed vaccine composed of a chimpanzee adenovirus viral vector expressing the RSV F, N, and M2-1 proteins (ChAd155-RSV) induced robust neutralizing antibody titers and interferon gamma (IFNγ)-secreting T cells compared to placebo controls ( 28 ). ReiThera Srl developed a similar vaccine using a chimpanzee adenovirus (PanAd3) viral vector expressing the RSV F, N, and M2-1 proteins in combination with a modified vaccinia virus Ankara (MVA).…”

Section: Rsv Vaccine Modalities and Lessons From The Host Immune Respmentioning

confidence: 99%

Current Insights in the Development of Efficacious Vaccines Against RSV

et al. 2020

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First-in-Human Randomized Study to Assess the Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus (RSV) Vaccine Based on Chimpanzee-Adenovirus-155 Viral Vector–Expressing RSV Fusion, Nucleocapsid, and Antitermination Viral Proteins in Healthy Adults

Cited by 46 publications

References 25 publications

A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

Innate Immune Responses to Chimpanzee Adenovirus Vector 155 Vaccination in Mice and Monkeys

Current Insights in the Development of Efficacious Vaccines Against RSV

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