Elsevier

Vaccine

Volume 38, Issue 6, 5 February 2020, Pages 1384-1392
Vaccine

Safety and immunogenicity of a 30-valent M protein-based group a streptococcal vaccine in healthy adult volunteers: A randomized, controlled phase I study

https://doi.org/10.1016/j.vaccine.2019.12.005Get rights and content

Abstract

Background

Streptococcus pyogenes (group A Streptococcus, Strep A) is a widespread pathogen that continues to pose a significant threat to human health. The development of a Strep A vaccine remains an unmet global health need. One of the major vaccine strategies is the use of M protein, which is a primary virulence determinant and protective antigen. Multivalent recombinant M protein vaccines are being developed with N-terminal M peptides that contain opsonic epitopes but do not contain human tissue cross-reactive epitopes.

Methods

We completed a Phase I trial of a recombinant 30-valent M protein-based Strep A vaccine (Strep A vaccine, StreptAnova™) comprised of four recombinant proteins containing N-terminal peptides from 30 M proteins of common pharyngitis and invasive and/or rheumatogenic serotypes, adjuvanted with aluminum hydroxide. The trial was observer-blinded and randomized in a 2:1 ratio for intramuscular administration of Strep A vaccine or an alum-based comparator in healthy adult volunteers, at 0, 30 and 180 days. Primary outcome measures were assessments of safety, including assays for antibodies that cross-reacted with host tissues, and immunogenicity assessed by ELISA with the individual vaccine peptides and by opsonophagocytic killing (OPK) assays in human blood.

Results

Twenty-three Strep A-vaccinated participants and 13 controls completed the study. The Strep A vaccine was well-tolerated and there was no clinical evidence of autoimmunity and no laboratory evidence of tissue cross-reactive antibodies. The vaccine was immunogenic and elicited significant increases in geometric mean antibody levels to 24 of the 30 component M antigens by ELISA. Vaccine-induced OPK activity was observed against selected M types of Strep A in vaccinated participants that seroconverted to specific M peptides.

Conclusion

The Strep A vaccine was well tolerated and immunogenic in healthy adults, providing strong support for further clinical development. [ClinicalTrials.gov NCT02564237].

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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