The Respiratory Syncytial Virus G Protein Conserved Domain Induces a Persistent and Protective Antibody Response in Rodents

Abstract

Respiratory syncytial virus (RSV) is an important cause of severe upper and lower respiratory disease in infants and in the elderly. There are 2 main RSV subtypes A and B. A recombinant vaccine was designed based on the central domain of the RSV-A attachment G protein which we had previously named G2Na (aa130–230). Here we evaluated immunogenicity, persistence of antibody (Ab) response and protective efficacy induced in rodents by: (i) G2Na fused to DT (Diphtheria toxin) fragments in cotton rats. DT fusion did not potentiate neutralizing Ab responses against RSV-A or cross-reactivity to RSV-B. (ii) G2Nb (aa130–230 of the RSV-B G protein) either fused to, or admixed with G2Na. G2Nb did not induce RSV-B-reactive Ab responses. (iii) G2Na at low doses. Two injections of 3 µg G2Na in Alum were sufficient to induce protective immune responses in mouse lungs, preventing RSV-A and greatly reducing RSV-B infections. In cotton rats, G2Na-induced RSV-reactive Ab and protective immunity against RSV-A challenge that persisted for at least 24 weeks. (iv) injecting RSV primed mice with a single dose of G2Na/Alum or G2Na/PLGA [poly(D,L-lactide-co-glycolide]. Despite the presence of pre-existing RSV-specific Abs, these formulations effectively boosted anti-RSV Ab titres and increased Ab titres persisted for at least 21 weeks. Affinity maturation of these Abs increased from day 28 to day 148. These data indicate that G2Na has potential as a component of an RSV vaccine formulation.

Recombinant influenza virus expressing a fusion protein neutralizing epitope of respiratory syncytial virus (RSV) confers protection without vaccine-enhanced RSV disease

“…We chose a dose of 2x10 5 PFU that was recently reported to be sufficient to assess the efficacy of RSV vaccines (Garg et al, 2014; Johnson et al, 2014; Kim et al, 2014; Murata and Catherman, 2012; Nguyen et al, 2012; Schmidt et al, 2012). We also found that the PBS or PR8 WT group of mice that were infected with 2x10 5 PFU RSV showed a high titer of approximately up to 10 4 PFU from lungs at day 5 post infection (Fig.…”

Structure and Function of Respiratory Syncytial Virus Surface Glycoproteins

“…These problems have been attributed to an Arthus reaction to the BB component (Libon 2007). Without the BB component, the G2Na peptide induced protective immunity in cotton rats and, in previously immunized mice, it was recently shown to boost antibody titer to RSV (Nguyen et al 2012), suggesting that this approach might work to boost immunity to RSV in older adults. Another group performed vaccination studies in naive mice with a similar peptide (amino acids 131–230) and mucosal immunization, without the addition of an adjuvant.…”

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

“…Based on these findings, strategies for developing a safer RSV vaccine that circumvents FI-RSV-induced VED should include the induction of both Treg cells in lung and high levels of neutralizing Abs (20,45,46). Among all of the 11 viral proteins of RSV, only G and F glycoproteins contain neutralizing epitopes and induce long-term neutralizing Abs (47)(48)(49). For this reason, both have been considered as ideal candidates for RSV vaccine development.…”