M2-2 Deletion Aids in Immunogenicity of RSV Vaccine in Children

The respiratory syncytial virus (RSV) vaccine attenuation strategy to delete M2-2 protein demonstrated immunogenicity and may be worth further evaluation, according to results of a study published in the Journal of Infectious Diseases.

An effective RSV vaccine could have a major positive effect on infants and children aged <5 years, because infection with this virus is a major cause of morbidity and mortality in this population. The key to a successful RSV vaccine is achieving high rates of immune response while maintaining attenuation. One promising attenuation strategy is the deletion of the open reading frame that encodes the RNA synthesis regulatory protein M202 in RSV because deletion of this protein results in decreased genome replication.

Two vaccine candidates with this deletion, MEDI/ΔM2-2 and LID/ ΔM2-2, were evaluated in children, and both induced strong RSV-neutralizing antibody responses and anamnestic antibody responses. However, MEDI/ΔM2-2 recipients showed a 100-fold lower peak titer of vaccine virus shed. Furthermore, in a phase 1 study, LID/ΔM2-2 was well tolerated but had higher replication, which may have caused it to be poorly tolerated when administered to large populations. D46/NS2/N/ΔM2-2-HindIII is a vaccine similar to the LID backbone, but with a phenotype similar to MEDI/ΔM2-2. Therefore, this randomized, double-blind, placebo-controlled study evaluated D46/NS2/N/ΔM2-2-HindIII in RSV-seronegative children (ClinicalTrials.gov identifiers: NCT03102034 and NCT03099291).

In total, 32 RSV-seronegative children aged 6 to 24 months were included and randomly assigned (1:2) to receive 1 intranasal dose (10⁵ PFU) of either placebo (n=11) or D46/NS2/N/ΔM2-2-HindIII (n=21). All participants were then monitored for vaccine shedding, reactogenicity, RSV-antibody responses, and RSV-associated medically-attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season.

Results suggested that the RSV D46/NS2/N/ΔM2-2-HindIII candidate was 100% immunogenic and well tolerated. All 21 participants who received the vaccine demonstrated an immunologic response (ie, shed vaccine and/or had a rise in serum RSV antibodies); 20 (95%) of these participants had vaccine virus detected by both immunoplaque assay and reverse transcription-quantitative polymerase chain reaction. Assessment of serum antibody responses to the vaccine at 2 months post-inoculation showed a ³4-fold rise in serum RSV PRNT₆₀ titers and anti-RSV F IgG titers in 20 (95%) and 21 (100%) of vaccine recipients, respectively, and none of the placebo recipients (P <.001). Natural RSV infection was observed in 6 vaccine recipients and 4 placebo recipients during the RSV season after vaccination. RSV-associated medically-attended acute respiratory illness was observed in 2 of these vaccine recipients and all these placebo recipients. However, serum RSV PRNT₆₀ titers were higher in the vaccine recipients compared with those who received the placebo (median, 10.4 vs 7.1), which suggested an anamnestic response to wildtype RSV. Mild upper respiratory and/or febrile events were observed during the 28 days post-inoculation in both the vaccine and placebo recipients (76% and 18%, respectively), and all were grade 1. One participant in each group experienced a grade 2 fever. No lower respiratory tract infections, serious adverse events, or ³ grade 3 events occurred.

“D46/NS2/N/ΔM2-2-HindIII vaccine had excellent [immunogenicity] and generated robust neutralizing antibody and anti-RSV F-protein [immunoglobulin G] responses,” the study authors wrote. They concluded: “This study provides further evidence of the safety and immunogenicity of live-attenuated RSV vaccines using a deletion mutation in M2-2 as the primary attenuating factor [and demonstrates] the feasibility and the promise of rational design for the iterative process to create a live-attenuated RSV vaccine.”

Reference

McFarland EJ, Karron RA, Muresan P, et al. Live-attenuated respiratory syncytial virus with [email protected] deletion and with SH non-coding region is highly immunogenic in children [published online February 1, 2020]. J Infect Dis. doi:10.1093/infdis/jaa049/5719572