Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial

Ruckwardt, Tracy J.; Morabito, Kaitlyn M.; Phung, Emily; Crank, Michelle C.; Costner, Pamela; Holman, LaSonji A.; Chang, Lauren; Hickman, Somia P.; Berkowitz, Nina M.; Gordon, Ingelise J.; Yamshchikov, Galina V.; Gaudinski, Martin R.; Lin, Bob C.; Bailer, Robert T.; Chen, Man; Ortega-Villa, Ana M.; Nguyen, Thuy‐Ai; Kumar, Abhinav; Schwartz, Richard; Kueltzo, Lisa A.; Stein, Judith A.; Carlton, Kevin; Gall, Jason; Nason, Martha; Mascola, John R.; Chen, Grace; Graham, Barney S.; Arthur, Anita; Cunningham, Jennifer; Eshun, Aba Mensima; Larkin, Brenda; Mendoza, Floreliz; Novik, Laura; Saunders, Jamie; Wang, Xiaolin; Whalen, William; Carter, Cristina; Hendel, Cynthia S.; Plummer, Sarah H.; Ola, Abidemi; Widge, Alicia T.; Florez, Maria Claudia Burgos; Le, Lam; Pittman, Iris; Rothwell, Ro Shauna; Trofymenko, Olga; Василенко, О. А.; Apte, Preeti; Hicks, Renunda; Cartagena, Cora Trelles; Williams, Pernell; Requilman, LaShawn; Tran, Colin; Bai, Shufeng; Carey, Elizabeth J.; Chamberlain, Amy L.; Chang, Ya-Chen; Chen, Mingzhong; Chen, Peifeng; Cooper, Jonathan M.; Fridley, Colleen; Ghosh, Mridul; Gollapudi, Deepika; Holland-Linn, Janel; Horwitz, Joe; Hussain, Althaf I.; Ivleva, Vera B.; Kaltovich, Florence; Leach, Kristin; Lee, Christopher; Liu, Amy; Liu, Xun; Manceva, Slobodanka D.; Menon, Amritha; Nagy, Attila; O’Connell, Sarah; Ragunathan, Rahul; Walters, Jennifer; Zhao, Zhong

doi:10.1016/s2213-2600(21)00098-9

Cited by 39 publications

(32 citation statements)

References 32 publications

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“…Durability of responses were demonstrated with neutralizing titer GMFRs remaining 3- to 4-fold above baseline levels in adults aged 65–85 years and 3- to 5-fold higher in adults aged 18–49 years through 12 months of study. These findings are comparable to those for another investigational RSV prefusion F subunit vaccine, which in adults aged 18–50 years elicited robust RSV neutralizing activity at week 4 postvaccination that remained ≥2.8-fold higher than baseline at week 44 [ 25 ]. Adsorption to Al(OH) 3 did not augment neutralizing responses to RSVpreF, similar to other investigational RSV F vaccines [ 25 , 26 ].…”

Section: Discussionsupporting

confidence: 81%

“…These findings are comparable to those for another investigational RSV prefusion F subunit vaccine, which in adults aged 18–50 years elicited robust RSV neutralizing activity at week 4 postvaccination that remained ≥2.8-fold higher than baseline at week 44 [ 25 ]. Adsorption to Al(OH) 3 did not augment neutralizing responses to RSVpreF, similar to other investigational RSV F vaccines [ 25 , 26 ]. Robust immunogenicity in older adults is particularly encouraging given the age-related reductions in antibody responses observed for other vaccines in this population, including influenza vaccines [ 27 ].…”

Section: Discussionsupporting

confidence: 81%

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Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults With Concomitant Inactivated Influenza Vaccine

Falsey

Walsh

Scott

et al. 2021

The Journal of Infectious Diseases

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Background Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults and adults with comorbidities. An effective vaccine is needed. An investigational bivalent prefusion F vaccine (RSVpreF) was assessed in healthy adults. Methods This phase 1/2 study randomized adults 18–85 years old to receive placebo or 60, 120, or 240 µg RSVpreF (with or without Al[OH]3) alone or concomitantly with seasonal inactivated influenza vaccine (SIIV). Safety and immunogenicity were assessed. Results In older adults, reactogenicity events were predominantly mild or moderate among RSVpreF recipients; adverse events through 1 month postvaccination were similar across formulations. Coadministration with SIIV did not appear to affect safety among younger or older adults. All RSVpreF formulations with or without concomitant SIIV elicited robust RSV serum neutralizing responses in adults 50–85 years 1 month postvaccination. Neutralizing titers 1 and 12 months postvaccination were 6.9–14.9- and 2.9–4.5-times, respectively, those before vaccination. SIIV immune responses trended lower when coadministered with RSVpreF. Conclusions RSVpreF formulations administered alone or with SIIV were well tolerated and highly immunogenic in older adults, supporting the potential for RSVpreF to protect older adults from RSV disease.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 81%

Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults With Concomitant Inactivated Influenza Vaccine

Falsey

Walsh

Scott

et al. 2021

The Journal of Infectious Diseases

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“…Regardless of the number of vaccinations, F-specific memory B cells remained elevated above baseline at the last study time point (week 44). These results, along with the sustained elevation of serum neutralizing activity elicited in this phase 1 trial, demonstrate that pre-F subunit vaccines could be administered in a one-dose regimen (18). Generating a long-lasting memory response with one immunization is particularly advantageous for vaccination in pregnant women and in the elderly.…”

Section: Discussionmentioning

confidence: 61%

Elicitation of pneumovirus-specific B cell responses by a prefusion-stabilized respiratory syncytial virus F subunit vaccine

et al. 2022

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Respiratory syncytial virus (RSV) is a substantial cause of morbidity and mortality globally. A candidate RSV prefusion (pre-F)–stabilized subunit vaccine, DS-Cav1, has previously been shown to elicit potent and durable neutralizing activity in a phase 1 clinical trial in healthy adults. Here, we used fluorescently labeled probes and flow cytometry to evaluate the antigen specificity and phenotype of RSV F–specific B cells longitudinally after DS-Cav1 immunization. Peripheral blood mononuclear cells (PBMCs) collected at time points before the first immunization through the end of the trial at 44 weeks were assessed by flow cytometry. Our data demonstrate a rapid increase in the frequency of pre-F–specific IgG + and IgA + B cells after the first immunization and a modest increase after a second immunization at week 12. Nearly all F-specific B cells down-regulated CD21 and up-regulated the proliferation marker CD71 after the first immunization, with less pronounced activation after the second immunization. Memory B cells (CD27 + CD21 + ) specific for pre-F remained elevated above baseline at 44 weeks after vaccination. DS-Cav1 vaccination also activated human metapneumovirus (HMPV) cross-reactive B cells capable of binding prefusion-stabilized HMPV F protein and increased HMPV F-binding antibodies and neutralizing activity for HMPV in some participants. In summary, vaccination with RSV pre-F resulted in the expansion and activation of RSV and HMPV F-specific B cells that were maintained above baseline for at least 10 months and could contribute to long-term pneumovirus immunity.

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“…The initial pre-F/G immunogen included both GCN4 and T4-phage fibritin (Fd) trimerization domains. Previously, DS-Cav1 protein, an RSV stabilized pre-F trimerized using the Fd trimerization domain, was evaluated in a Phase I clinical trial (VRC 317) ( 75 , 76 ). Therefore, we aimed to evaluate immunogens that incorporated only GCN4 or Fd for stability and immunogenicity.…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned previously, mRNA delivery of vaccine antigens has been well tolerated in humans (64)(65)(66). The NiV pre-F antigen has not been tested in humans but extensive testing of a prefusion stabilized RSV F protein containing the foldon trimerization domain (DS-Cav1) has been evaluated in a Phase I clinical trial with no toxicity reported from the protein antigen (75,76). A Hendra soluble G protein is currently under evaluation in a Phase I clinical trial, but data on toxicity has not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine

et al. 2021

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Nipah virus (NiV) represents a significant pandemic threat with zoonotic transmission from bats-to-humans with almost annual regional outbreaks characterized by documented human-to-human transmission and high fatality rates. Currently, no vaccine against NiV has been approved. Structure-based design and protein engineering principles were applied to stabilize the fusion (F) protein in its prefusion trimeric conformation (pre-F) to improve expression and increase immunogenicity. We covalently linked the stabilized pre-F through trimerization domains at the C-terminus to three attachment protein (G) monomers, forming a chimeric design. These studies detailed here focus on mRNA delivery of NiV immunogens in mice, assessment of mRNA immunogen-specific design elements and their effects on humoral and cellular immunogenicity. The pre-F/G chimera elicited a strong neutralizing antibody response and a superior NiV-specific Tfh and other effector T cell response compared to G alone across both the mRNA and protein platforms. These findings enabled final candidate selection of pre-F/G Fd for clinical development.

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Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial

Cited by 39 publications

References 32 publications

Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults With Concomitant Inactivated Influenza Vaccine

Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults With Concomitant Inactivated Influenza Vaccine

Elicitation of pneumovirus-specific B cell responses by a prefusion-stabilized respiratory syncytial virus F subunit vaccine

Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine

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