Immunological Lessons from Respiratory Syncytial Virus Vaccine Development

Background Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). Methods We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). Results There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. Conclusions Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. Clinical trials registration NCT02325791. https://clinicaltrials.gov/ct2/show/NCT02325791.

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Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of outpatient visits, which result in a huge economic and healthcare burden. Most hospitalizations happen in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence on the association between early-life RSV respiratory illness and recurrent wheezing/asthma-like symptoms As such, RSV is considered a global health priority. However, despite this, the only prevention strategy currently available is palivizumab, a monoclonal antibody (mAb) indicated in a subset of preterm infants or those with comorbidities, hence leaving the majority of the infant population unprotected against this virus. Therefore, development of prevention strategies against RSV for all infants entering their first RSV season constitutes a large unmet medical need. The aim of this review is to explore different immunization approaches to protect all infants against RSV. Prevention strategies include maternal immunization, immunization of infants with vaccines, immunization of infants with licensed mAbs (palivizumab), and immunization of infants with long-acting mAbs (e.g., nirsevimab, MK-1654). Of these, palivizumab use is restricted to a small population of infants and does not offer a solution for all-infant protection, whereas vaccine development in infants has encountered various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will most likely be used in older infants (>6 months of age) and children. Consequently, maternal immunization and immunization of infants with long-acting mAbs represent the two feasible strategies for protection of all infants against RSV. Here, we present considerations regarding these two strategies covering key areas which include mechanism of action, “consistency” of protection, RSV variability, duration of protection, flexibility and optimal timing of immunization, benefit for the mother, programmatic implementation, and acceptance of each strategy by key stakeholders. We conclude that, based on current data, immunization of infants with long-acting mAbs might represent the most effective approach for protecting all infants entering their first RSV season.

RSV Prevention in All Infants: Which Is the Most Preferable Strategy?

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months of age worldwide; therefore, the prevention of RSV infection in all infants represents a significant unmet medical need. Here we report the isolation of a potent and broadly neutralizing RSV monoclonal antibody derived from a human memory B-cell. This antibody, RB1, is equipotent on RSV A and B subtypes, potently neutralizes a diverse panel of clinical isolates in vitro and demonstrates in vivo protection. It binds to a highly conserved epitope in antigenic site IV of the RSV fusion glycoprotein. RB1 is the parental antibody to MK-1654 which is currently in clinical development for the prevention of RSV infection in infants.

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A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein

Human respiratory syncytial viruses (RSVs) are classified into two major groups (A and B) based on antigenic differences in the G glycoprotein. To investigate circulating characteristics and phylodynamic history of RSV, we analyzed the genetic variability and evolutionary pattern of RSVs from 1977 to 2019 in this study. The results revealed that there was no recombination event of intergroup. Single nucleotide polymorphisms (SNPs) were observed through the genome with the highest occurrence rate in the G gene. Five and six sites in G protein of RSV-A and RSV-B, respectively, were further identified with a strong positive selection. The mean evolutionary rates for RSV-A and -B were estimated to be 1.48 × 10-3 and 1.92 × 10-3 nucleotide substitutions/site/year, respectively. The Bayesian skyline plot showed a constant population size of RSV-A and a sharp expansion of population size of RSV-B since 2005, and an obvious decrease 5 years later, then became stable again. The total population size of RSVs showed a similar tendency to that of RSV-B. Time-scaled phylogeny suggested a temporal specificity of the RSV-genotypes. Monitoring nucleotide changes and analyzing evolution pattern for RSVs could give valuable insights for vaccine and therapy strategies against RSV infection.

/pdf/genetic-diversity-and-molecular-evolution-of-human-3j2mezfpef.pdf

Genetic diversity and molecular evolution of human respiratory syncytial virus A and B.

Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infection in infants and elderly. To understand the evolution of neutralizing epitopes on the RSV glycoprotein (G) and fusion (F) proteins, we conducted a multi-year surveillance program (OUTSMART-RSV) in the US. Analysis of 1,146 RSV samples from 2015–2017 revealed a slight shift in prevalence from RSV A (58.7%) to B (53.7%) between the two seasons. RSV B was more prevalent in elderly (52.9% and 73.4%). Approximately 1% of the samples contained both RSV A and B viruses. All RSV A isolates were ON1 and almost all the B isolates were BA9 genotypes. Compared with the 2013 reference sequences, changes at the F antigenic sites of RSV B were greater than RSV A, which mainly occurred at antigenic sites V (L172Q/S173L at 99.6%), O (I206M/Q209K at 18.6%) and IV (E463D at 7%) of RSV B F. Sequence diversities in the G protein second hypervariable region were observed in the duplicated regions for RSV A and B, and at the G stop codon resulting in extension of 7 amino acids (22.1%) for RSV B in 2016–17. Thus, RSV surface glycoproteins are continuously evolving, and continued surveillance is important for the clinical evaluation of immunoprophylactic products.

Emergence of new antigenic epitopes in the glycoproteins of human respiratory syncytial virus collected from a US surveillance study, 2015-17.

BACKGROUND Respiratory syncytial virus (RSV) is an established cause of serious lower respiratory disease in infants, elderly and high-risk populations. The OUTSMART surveillance program aims to characterize patient populations and currently circulating RSV strains, and monitor temporal and geographic evolution of RSV F and G proteins in the U.S. METHODS The OUTSMART 2016-17 study collected RSV-positive samples from 25 RSVAlert® laboratories from 4 U.S. regions and Puerto Rico during November 2016 through March 2017. Frequencies of A and B subtypes and genotypes were determined for several demographic and geographic variables. To gauge the representativeness of the OUTSMART patients, results were compared to discharge data from the NEDS and NIS databases. RESULTS A total of 1,041 RSV-positive samples with associated demographic data were obtained and the RSV F gene and second variable region of the G gene were sequenced. The majority of samples (76.0%) came from children under 2 years old: 24 hrs) occurred in 29.0% of patients of which 52.0% had RSV B. Outpatients (LOS <24 hrs) were 64.4% of total of which 73.3% were diagnosed in the ER and discharged, while only 6% were diagnosed in other outpatient settings. CONCLUSIONS The OUTSMART 2016-17 study was representative of the U.S. RSV experience. Geographic and temporal information from the RSV surveillance program will be used to establish a molecular baseline of RSV F and G sequence variability and to help inform development of novel agents for RSV prophylaxis and treatment.

/pdf/characterization-of-circulating-rsv-strains-among-subjects-aq6h4d4s0m.pdf

Characterization of circulating RSV strains among subjects in the OUTSMART-RSV surveillance program during the 2016-17 winter viral season in the United States

Background RSV is a leading cause of lower respiratory tract infection in infants. Monitoring RSV glycoprotein sequences is critical for understanding RSV epidemiology and viral antigenicity in the effort to develop anti-RSV prophylactics and therapeutics. Objectives The objective is to characterize the circulating RSV strains collected from infants in South Africa during 2015-2017. Methods A subset of 150 RSV-positive samples obtained in South Africa from HIV-unexposed and HIV-exposed-uninfected infants from 2015 to 2017, were selected for high-throughput next-generation sequencing of the RSV F and G glycoprotein genes. The RSV G and F sequences were analyzed by a bioinformatic pipeline and compared to the USA samples from the same three-year period. Results Both RSV A and RSV B co-circulated in South Africa during 2015-2017, with a shift from RSV A (58%-61% in 2015-2016) to RSV B (69%) in 2017. RSV A ON1 and RSV B BA9 genotypes emerged as the most prevalent genotypes in 2017. Variations at the F protein antigenic sites were observed for both RSV A and B strains, with dominant changes (L172Q/S173L) at antigenic site V observed in RSV B strains. RSV A and B F protein sequences from South Africa were very similar to the USA isolates except for a higher rate of RSV A NA1 and RSV B BA10 genotypes in South Africa. Conclusion RSV G and F genes continue to evolve and exhibit both local and global circulation patterns in South Africa, supporting the need for continued national surveillance.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/irv.12727

Characterization of human respiratory syncytial virus (RSV) isolated from HIV-exposed-uninfected and HIV-unexposed infants in South Africa during 2015-2017.

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Emergence of new antigenic epitopes in the glycoproteins of human respiratory syncytial virus collected from a US surveillance study, 2015-17.

Characterization of circulating RSV strains among subjects in the OUTSMART-RSV surveillance program during the 2016-17 winter viral season in the United States

Characterization of human respiratory syncytial virus (RSV) isolated from HIV-exposed-uninfected and HIV-unexposed infants in South Africa during 2015-2017.