An investigational 24-valent pneumococcal conjugate vaccine (PCV) (VAX-24, Vaxcyte) developed on a novel cell-free protein synthesis platform appears in a phase 1/2 trial1 to be the first to target this number of pneumococcal serotypes without reduction in immunogenicity.
"VAX-24 is an improved PCV that for the first time, provides the ability to simultaneously achieve both higher serotype valency and enhanced immune response," said Vaxcyte Chief Operating Officer James Wassil, MS.
In an announcement,2 of the study issued by Vaxcyte, Wassil describes thefindings as a testament "to the potential of our cell-free technology to create carrier-sparing conjugate vaccines that provide broader coverage with enhanced immunogenicity compared to the standard-of-care in adults today."
Wassil and colleague explain why previous attempts to add valency without compromising immune response using conventional technology have been challenging.
"First, as more carrier protein-polysacccharide conjugates are added to existing PCV, immune responses to the polysaccharide generally decrease due to the cumulative amount of carrier protein, which competes immunologically—eg, for CD4 help—with the polysaccharide antigens."
"Second, randomly conjugating additional polysaccarides to a carrier protein mulecule might mask existing T-cell epitopes, which are critically important in eliciting an immune response," they pointed out.
What You Need to Know
VAX-24 is developed on a novel cell-free protein synthesis platform, making it the first pneumococcal conjugate vaccine to target 24 serotypes without a reduction in immunogenicity.
Conventional attempts to increase valency without compromising immune response faced challenges. The cumulative amount of carrier protein in existing PCVs could decrease immune responses to polysaccharides.
The dose-finding, active-controlled clinical trial involving 835 healthy adults showed favorable results, leading to the FDA granting Fast Track and Breakthrough designation to VAX-24 in January 2023.
The favorable results from this dose-finding, active-controlled clinical trial along with preclinical testing were sufficient for the FDA to grant the vaccine Fast Track and Breakthrough designation in January 2023. The designation is intended to expedite development and review of drugs to treat serious or life-threatening conditions.
The trial randomized 835 healthy adults to receive a single dose of either the commercially available comparator PCV20, or VAX-24 with 1.1mcg of total pneumococcal polysaccharides per dose per serotype (PnPS); 2.2mcg PnPS; or a mix of 2.2mcg for 17 serotypes and 4.4mcg for serotypes 3, 6B, 7F, 9V, 18C, 19A and 19F.
Serotypes are selected for a vaccine from the 100 known serotypes of Streptococcus pneumoniae with consideration that not all are pathogenic and approximately one-third are not considered epidemiologically relevant. The PCV 20 comparator contains the same serotypes as VAX-24, with the exception of serotypes 2, 9N, 17F, and 20B; and contains 2.2mcg PnPS per dose for each except for 4.4mcg against 6B.
In addition to assessing safety and tolerability though solicited and unsolicited adverse event reports, the investigators ascertained serotype-specific functional antibody responses with OPA (opsonophagocytosis assay) and IgG levels.
"OPA, mediated by antibodies and complement, has been consistently used as the method for measuring the functional capacity of pneumococcal antibodies," Wassil and colleagues explain, "as antibodies to PnPS protect the host by opsonising pneumococci—marking pneumococci for destruction—for phagocytosis."
The investigators reported that the 2.2mcg VAX-24 met traditional OPA GMR (geometric mean ratios) non-inferiority criteria for all 20 shared serotypes; and that IgG GMC (geometric mean concentrations) were similar to those for OPA. Safety profiles were comparable among the treatment groups.
"The results from the proof-of-concept study provided the first look at the safety and immunogenicity profile of VAX-24 in adults, giving us confidence in the 2.2mcg dose we plan to advance into phase 3," stated Vaxcyte Chief Medical Officer Jakub Simon, MD, MS, in the manufacturer's announcement.2
In an editorial accompanying publication of the trial results, Beth Temple, MSc, Infection and Immunity, and Paul Licciardi, PhD, Vaccine Immunology, Murdoch Children's Research Institute, Melbourne, VIC, Australia, recognize the potential of PCVs that increase valency without reducing immunogenicity, but express concern that there is no standard way to assess responses to the additional unique serotypes.3
"The new technology in VAX-24 could offer one solution to this problem, although it is essential that a standardized methodology is established for evaluating new products as they become available," they advise.3
1. Wassil J, Sisti M, Fairman J, et al.Evaluating the safety, tolerability, and immunogenicity of a 24-valent pneumococcal conjugate vaccine (VAX-24) in healthy adults aged 18 to 64 years: a phase 1/2, double-masked, dose-finding, active-controlled, randomised clinical trial. Lancet Infect Dis Published online December 4, 2023. https://doi.org/10.1016/S1473-3099(23)00572-8. Accessed December 16, 2023.
2. Vaxcyte. VAX-24 Phase 1/2 Adult Proof-of-Concept Data Published in The Lancet Infectious Diseases Highlight Best-in-Class Potential of Vaxcyte’s 24-Valent Pneumococcal Conjugate Vaccine (PCV) Candidate. Press release, December 4, 2023. https://investors.vaxcyte.com/news-releases/news-release-details/vax-24-phase-12-adult-proof-concept-data-published-lancet.Accessed December 16, 2023.
3. Temple B, Licciardi P. Is it time to reconsider how higher valency pneumococcal conjugate vaccines are evaluated? Lancet Infect Dis Published online December 4, 2023. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00634-5/fulltext. Accessed December 16, 2023.