Live Respiratory Syncytial Virus Attenuated by M2-2 Deletion and Stabilized Temperature Sensitivity Mutation 1030s Is a Promising Vaccine Candidate in Children

Abstract

Background The safety and immunogenicity of live respiratory syncytial virus (RSV) candidate vaccine, LID/ΔM2-2/1030s, with deletion of RSV ribonucleic acid synthesis regulatory protein M2-2 and genetically stabilized temperature-sensitivity mutation 1030s in the RSV polymerase protein was evaluated in RSV-seronegative children. Methods Respiratory syncytial virus-seronegative children ages 6–24 months received 1 intranasal dose of 105 plaque-forming units (PFU) of LID/ΔM2-2/1030s (n = 21) or placebo (n = 11). The RSV serum antibodies, vaccine shedding, and reactogenicity were assessed. During the following RSV season, medically attended acute respiratory illness (MAARI) and pre- and postsurveillance serum antibody titers were monitored. Results Eighty-five percent of vaccinees shed LID/ΔM2-2/1030s vaccine (median peak nasal wash titers: 3.1 log10 PFU/mL by immunoplaque assay; 5.1 log10 copies/mL by reverse-transcription quantitative polymerase chain reaction) and had ≥4-fold rise in serum-neutralizing antibodies. Respiratory symptoms and fever were common (60% vaccinees and 27% placebo recipients). One vaccinee had grade 2 wheezing with rhinovirus but without concurrent LID/ΔM2-2/1030s shedding. Five of 19 vaccinees had ≥4-fold increases in antibody titers postsurveillance without RSV-MAARI, indicating anamnestic responses without significant illness after infection with community-acquired RSV. Conclusions LID/ΔM2-2/1030s had excellent infectivity without evidence of genetic instability, induced durable immunity, and primed for anamnestic antibody responses, making it an attractive candidate for further evaluation.

The immunogenicity and safety of respiratory syncytial virus vaccines in development: A systematic review

“…In the follow‐up RSV season, RSV‐MAARI were found in 1 vaccinee vs 2 placebo recipients. Thus, this vaccine candidate was promising in children 18 . McFarland et al reported on two studies (NCT03102034 and NCT03099291).…”

“…The relevant data were pooled from LID∆M2‐2, MEDI M2‐2, RSVcps2, LID/∆M2‐2/1030s and RSV/NS2/1313/I1314L 15,18,22,29,63 . All these candidates were live‐attenuated vaccine candidates examined in young children.…”

Current State and Challenges in Developing Respiratory Syncytial Virus Vaccines

“…LID/cp/ΔM2-2, designed with the insertion of a set of five defined point mutations originally derived from serial cold passage, resulted in an over-attenuated vaccine that had low infectivity and low-titre antibodies in only a fraction of the participants, thus being not suitable for further development [ 97 ]. Another vaccine constructed by the addition of the genetically stabilized mutation 1030s, LID/ΔM2-2/1030s, was investigated in a Phase I study [ 98 ]. This candidate was more attenuated than the parent vaccine with vaccine-induced titres of serum RSV-neutralizing antibodies, essentially equivalent to a primary RSV infection [ 98 ].…”

“…Another vaccine constructed by the addition of the genetically stabilized mutation 1030s, LID/ΔM2-2/1030s, was investigated in a Phase I study [ 98 ]. This candidate was more attenuated than the parent vaccine with vaccine-induced titres of serum RSV-neutralizing antibodies, essentially equivalent to a primary RSV infection [ 98 ]. These characteristics make this candidate very attractive for further investigations.…”

Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long Live Attenuated Vaccine Candidates

“…Therefore, safety is set as the priority for the development of RSV vaccine for infants, and avoiding ERD as well as stimulating effective immune protection are still the main challenges of RSV vaccine research. One of the promising candidates is the RSV live attenuated vaccine (LAV), which has been successfully obtained by introducing mutations or/and deleting non-essential genes from the RSV genome (Connors et al 1995;McFarland et al 2018;McFarland et al 2020a;McFarland et al 2020b). Among the dispensable genomic regions are genes encoding small hydrophobic protein (SH), nonstructural proteins (NS), and M2 ORF protein 2 (M2-2) proteins.…”