Safety and immunogenicity of a 30-valent M protein-based group a streptococcal vaccine in healthy adult volunteers: A randomized, controlled phase I study
Introduction
Group A Streptococcal (Strep A) infections remain an important cause of morbidity and mortality throughout the world [1]. Previous reports estimate that more than 500,000 individuals die each year as a result of Strep A infections or their complications [2]. A large part of this mortality is due to rheumatic heart disease (RHD) in low- and middle-income countries [3]. In addition to RHD, the disease burden of S. pyogenes infections includes serious invasive infections, such as bacteremia, pneumonia, streptococcal toxic shock, necrotizing fasciitis, and puerperal sepsis, as well as the non-invasive infections, impetigo and pharyngitis. In 2015, the Product Development Vaccine Advisory Committee of the World Health Organization (WHO) recognized the feasibility of developing an effective Strep A vaccine and recommended that investment cases be established for low- and high-income countries [4]. Subsequently, the WHO published a Group A Strep Vaccine Research and Development Roadmap and a Preferred Product Characteristics document [5]. The World Health Assembly recently adopted a resolution calling for greater action on RHD, encouraging international stakeholders to support research that will impact the disease [6].
Efforts to develop a Strep A vaccine have been ongoing for nearly a century. The surface-expressed M protein is a major Strep A protective antigen and a principal target for vaccine development. Numerous experimental M protein-based vaccines, ranging from crude cell walls to highly purified M proteins, were evaluated between the 1930s and 1970s in trials involving thousands of participants [7]. Vaccine development was essentially halted when a trial in the 1960s that assessed a partially purified M3 protein vaccine showed an apparent increase in the attack rate of rheumatic fever among vaccinated children compared to historical controls [8], [9], although the causality of the association with the vaccine remains uncertain. In the 1980s, vaccine development efforts were revitalized after studies showed that type-specific amino-terminal regions of the M protein elicited the strongest bactericidal immune responses and could be separated from the potentially harmful cross-reactive epitopes [10], [11], [12]. These observations provided the rationale for creating multivalent Strep A vaccines. Complex hybrid proteins that contained increasing numbers of amino-terminal M protein fragments were evaluated in preclinical studies [10], [11], [12], [13] and in early-phase clinical trials [14], [15], [16]. StreptAvax, a 26-valent vaccine candidate was shown to be safe, well tolerated and immunogenic in phase I and II trials [15], [16]. The development of this promising candidate was halted for commercial reasons. The 30-valent Strep A vaccine, a new vaccine candidate that includes M peptides from 30 M (or emm) types was developed based on more recent epidemiological data [17]. We report here the results of the first safety and immunogenicity study of the 30-valent Strep A vaccine in healthy adult volunteers.
Section snippets
Study design
This was a randomized, comparator vaccine controlled, observer-blinded clinical trial conducted at one study site (Fig. 1). The trial was registered at www.ClinicalTrials.gov (NCT02564237). Randomization was based on a computer-generated list of random numbers using PROC PLAN in SAS® version 9.4. Overall, participants were randomized 2:1 to study vaccine or comparator vaccine. The first three participants were randomly assigned in a ratio of 2:1 to the test vaccine or comparator group. The
Demographic data
A total of 52 participants were screened (Fig. 1). Thirty-nine met eligibility requirements and were enrolled in the study. Screening failures were due to voluntary withdrawal before consent (N = 2), meeting echocardiogram exclusion criteria (N = 4), antibiotic treatment due to skin infection (N = 1), inability to undergo echocardiogram due to obesity (N = 1), abnormal screening blood (N = 2) or urinalysis results (N = 2), and a pre-existing condition (N = 1). Thirty-six participants received
Discussion
Vaccine prevention of Strep A infections and their complications has the potential to significantly reduce morbidity and mortality associated with serious infections and RHD, as well as health care costs and antibiotic use (mainly in high-income countries) associated with uncomplicated streptococcal pharyngitis and pyoderma. The development of Strep A vaccines has been ongoing for decades and progress has been made in the design and clinical testing of several recombinant multivalent M
Conclusions
Given the results of the current study and previous clinical experience with multivalent M protein-based vaccines, we think that further clinical development is warranted. To date, 151 adult volunteers have received multivalent M protein-based vaccines in four clinical studies [14], [15], [16]. In all cases, the vaccines were safe, well tolerated, and immunogenic. Importantly, there have been no autoimmune responses to the vaccines, nor was there clinical evidence of autoimmune complications
CRediT authorship contribution statement
Élodie Pastural: Methodology, Supervision, Writing - original draft. Shelly A. McNeil: Conceptualization, Methodology, Investigation, Supervision, Writing - review & editing. Donna MacKinnon-Cameron: Methodology, Data curation, Formal analysis, Writing - review & editing. Lingyun Ye: Data curation, Formal analysis. Joanne M. Langley: Investigation. Robert Stewart: Investigation. Luis H. Martin: Resources, Project administration, Funding acquisition. Gregory J. Hurley: Resources, Investigation.
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elodie Pastural is a former project manager for PREVENT, a funder of the study. Luis H. Martin is a former officer of PREVENT. Scott Halperin is a member of the Board of Directors of PREVENT. James B. Dale is an inventor on patent applications licensed to, and owns shares of, Vaxent, a funder of the study.
The other authors declare that they have no known
Acknowledgments
We thank the volunteers who participated in this study; Dr. Alan Mast, Wesley Zwifelhofer and Dr. Susan Maroney at the Blood Research Institute at Blood Center of Wisconsin for the human tissue cross-reactive antibody assays; Dr. Tammy Keough-Ryan (MD, FRCPC, Professor of Medicine, Division of Nephrology, Nova Scotia Health Authority, Dalhousie University) for her assistance with the blinded adjudication of potential renal adverse events; Catherine Brown (study coordinator), Dr. May ElSherif
Funding
Financial support was provided by Pan-Provincial Vaccine Enterprise Inc. (PREVENT), Canada and Vaxent, LLC, United States. The sponsors provided the study vaccine and provided some input into the study design. Tissue cross-reactive antibody assays were performed under a contract from the National Institutes of Health, United States (NIAID Contract HHSN272201200003I), to Dr. Mast at the Blood Research Institute at the Blood Center of Wisconsin. Dr. Dale received funds from the US Public Health
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