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 identify one or two lead candidates suitable for further development as an intranasal pediatric RSV vaccine. (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 Pasteur, Inc. To date, our clinical trials have focused on live-attenuated RSV strains. We will evaluate two PIV-vectored vaccines in the clinic in 2022. One lineage of live-attenuated RSV vaccine candidates involves deletion of the ORF encoding the small (90 amino acids) viral M2-2 protein. 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. Prototype delM2-2 candidates called RSV MEDI/delM2-2 and RSV LID/delM2-2 were evaluated and reported upon in past years. Last year, two reports on delM2-2 candidates were published, RSV LID/delM2-2/1030s (NCT02794870 and NCT0252339) and D46/NS2/N/delM2-2-HindIII (NCT03099291 and NCT03102034). Among these 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. A larger study in RSV seronegative children has been initiated this year. A second lineage of RSV vaccine candidates contains 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. This vaccine is being evaluated in a Phase 1/2 study in a head-to-head comparison with a second delNS2-based vaccine candidate, RSV delNS2/1030s. This virus combines the delNS2 mutation with a stabilized missense mutation called 1030s that consists of Y1321K and S1313(TCA) mutations in the L polymerase. The 1030s mutation is somewhat less attenuating than the del1313/I1314L mutation, and therefore RSV delNS2/1030s should be less attenuated than RSV/NS2/1313/I1314L. The RSV delNS2/1030s and RSV/NS2/1313/I1314L candidates are presently being evaluated head-to-head in a Phase 1/2 clinical trial in seronegative infants and young children (NCT03916185). 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). Participants from seven Phase 1 studies were surveilled during the subsequent winter RSV season to measure serum RSV-neutralizing antibody titers at the beginning and end of the winter, and to monitor respiratory illness during the winter and identify causative agents by nasal wash and RT-PCR. Without going into detail, this surveillance has provided presumptive evidence of protection against wild-type RSV infection, and shown that live-attenuated vaccine candidates prime for strong anamnestic RSV-specific antibody responses. RSV serum neutralizing antibody responses were identified as the most suitable correlate of vaccine take and possible predictors of efficacy. These observations are very encouraging. cDNA-derived RSV strain A2 is presently being evaluated in healthy adult volunteers in a dose-escalation study (NCT02484417). We also are evaluating a recent clinical isolate RSV A/Maryland/001/11 for which we have developed a reverse genetic system and recovered a recombinant virus in a Phase 1 trial 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.