Clinical Trials of Vaccines for Respiratory Syncytial Virus and Related Viruses

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

We are following two strategies to develop a live-attenuated pediatric RSV vaccine. (i) Our primary strategy is to develop live-attenuated RSV strains, with attenuation provided mainly by deletion of one of several nonessential genes and by missense and codon-deletion mutations that are mainly in the L polymerase and have been stabilized against de-attenuation using reverse genetics. The immediate goal is to advance lead candidates of intranasal pediatric RSV vaccines through larger clinical studies. (ii) A secondary vaccine strategy is to use attenuated versions of PIV3 as vectors to express RSV antigen (primarily the fusion F protein) which provide live bivalent HPIV3/RSV vaccines. The pre-clinical development of these PIV-vectored vaccines is described in the accompanying report "Laboratory and Pre-Clinical Studies of Parainfluenza Viruses". Both vaccine strategies are being developed under a Cooperative Research and Development Agreement (CRADA) with Sanofi. To date, our clinical trials have focused on live-attenuated RSV strains. In addition, we have evaluated two PIV-vectored vaccines in a pediatric Phase 1 study. One lineage of live-attenuated RSV vaccine candidates involves deletion of the ORF encoding the small (90 amino acids) viral M2-2 protein (delM2-2). The M2-2 protein plays a role in regulating RSV RNA synthesis, and its deletion results in down-regulated viral RNA replication (causing viral attenuation) and a global up-regulation of viral gene transcription and antigen synthesis. Increased antigen expression per genome raises the possibility of increased immunogenicity per infectious particle. Among several delM2-2 candidates, LID/delM2-2/1030s emerged as the most promising virus. It is attenuated through deletion of M2-2, combined with a stabilized missense mutation called 1030s that consists of Y1321K and S1313(TCA) mutations in the L polymerase. In a Phase 1 study in 6-24 months-old RSV seronegative children, LID/delM2-2/1030s was well tolerated, had excellent infectivity without evidence of genetic instability, induced durable immunity, and primed for strong anamnestic antibody responses to wildtype RSV infection, making it an attractive candidate for further evaluation. Over the 2022 through 2025 fiscal years, a larger study to further evaluate the safety and immunogenicity of LID/delM2-2/1030s in RSV seronegative children was performed. This study is now closed. Sample and data analysis have been completed, and a publication is in preparation. A second lineage of RSV vaccine candidates contains a deletion of the NS2 gene, whose encoded protein antagonizes host interferon and apoptosis responses to viral infection. The candidate RSV delNS2/del1313/I1314L contains the delNS2 mutation combined with a mutation called del1313/I1314L comprising deletion of codon 1313 in the L polymerase plus an adjacent missense mutation I1314L that stabilizes against de-attenuation. In the 2025 FY, we completed the evaluation of the safety and immunogenicity of RSV delNS2/del1313/I1314L in 4-6 month-old infants, and a manuscript is in preparation. In addition, this vaccine candidate advanced to a larger dose-finding study, performed by our CRADA partner Sanofi (under our CRADA with Sanofi). Their phase I/II, randomized placebo-controlled, multicenter, dose finding trial evaluated the RSV delNS2/del1313/I1314L vaccine in participants 6–18 months of age, not pre-screened for pre-existing RSV antibodies. Participants received a low or a high dose (LD or HD) of the vaccine or placebo intranasally. The study enrolled 259 participants, including 66.7% RSV-naïve participants. The RSV delNS2/del1313/I1314L vaccine demonstrated an acceptable safety and a promising immunogenicity profile at both dose levels, supporting further development by our CRADA partner. (NCT04491877). A third lineage of RSV vaccine candidates contains a deletion of the NS1 gene that, like NS2, encodes a protein that antagonizes host interferon and apoptosis responses, but does so more efficiently than NS2 and thus might confer a phenotype that is more attenuated and immunogenic. Two viruses were made that each contain the delNS1 deletion as the sole attenuating element, but in one virus the F and G genes have been moved to the first and second genome positions in order to increase their expression (RSV 6120/delNS1 and 6120/F1G2/delNS1, respectively). These viruses presently are being compared head-to-head in a Phase 1 clinical trial (NCT03596801). In the 2025 fiscal year, we have also continued the evaluation of a recent clinical isolate RSV A/Maryland/001/11 for which we have developed a reverse genetic system and recovered a recombinant virus. Clinical study material was prepared and evaluated in a Phase 1 human challenge study in healthy adult volunteers (NCT03624790). These studies will provide an infection model that can be used to evaluate RSV therapeutic candidates and adult RSV vaccine candidates, and to study viral pathogenesis and the host response. As described under goals and objectives, the burden of HMPV and HPIV3 illness in children is substantial. HMPV is usually detected in about one-third or half of the numbers of hospitalizations due to RSV. Clinical presentation of HMPV is similar to that of RSV. Parainfluenza viruses also account for a substantial burden of lower respiratory illness in children under two years of age. In the 2025 fiscal year, we have evaluated live intranasal vaccine candidates based on a chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) vector designed to express the HMPV F protein in a phase 1 clinical study in HPIV3 seropositive children. These candidate vaccines represent bivalent vaccines to protect against HPIV3 and HMPV. The vaccine vector B/HPIV3 was developed previously in our lab and is a live chimeric parainfluenza virus type 3 that contains the N, P, M and L genes of bovine PIV3 (strain Kansas), and the fusion (F) and hemagglutinin-neuraminidase (HN) genes of human PIV3 (HPIV3; strain JS). The B/HPIV3 vector is attenuated in humans due to the host-range restriction conferred by the N, P, M, and L genes derived from bovine PIV3. A blinded, randomized, placebo-controlled study is currently ongoing to evaluate the safety of a single intranasal dose of two versions of B/HPIV3 expressing HMPV F proteins in HPIV3-seropositive participants (NCT06546423). If these candidates are well-tolerated in HPIV3 seropositive children, their safety and immunogenicity will be evaluated in HPIV3 seronegative children. We also compared the infectivity and immunogenicity of live-attenuated RSV vaccines in human immunodeficiency virus (HIV) exposed uninfected (HEU) and HIV-unexposed, uninfected (HUU) children. The analysis was based on results from clinical trials of 7 live-attenuated, intranasal RSV vaccines conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network among children 6 to <25 months of age with serum RSV-neutralizing titers of <1:40. Of 156 children, 90 (58%) were HUU and 66 (42%) were HEU. Seventy-six (84%) HUU and 63 (95%) HEU participants were infected with vaccine (i.e., shed vaccine virus and/or had a ≥4-fold rise in serum RSV antibodies at 56 days after vaccination). HUU children had higher serum RSV-neutralizing and anti-RSV F IgG titers prior to vaccination. Compared to HEU children, lower percentages of HUU children had ≥4-fold rises in RSV-neutralizing (67% vs 88%) and anti-RSV F IgG (70% vs 89%) titers at 56 days after vaccination. Thus, live-attenuated RSV vaccines are highly immunogenic in HEU children. Given their increased burden of RSV disease and higher early childhood mortality in some settings, HEU children should be prioritized for vaccination against RSV as these vaccines become available.