NEW YORK (Reuters Health) - A hexavalent group A streptococcal vaccine based on recombinant immunogens is safe and well tolerated, and capable of inducing vigorous bactericidal immune responses, according to phase I trial results reported in the Journal of the American Medical Association for August 11.
However, safety concerns regarding potential cross-reaction with human tissues mean that years of study remain before a group A streptococcal (GAS) vaccine will be ready for approval, Dr. Michael E. Pichichero maintains in an accompanying editorial.
“It has been about 30 years since a streptococcal vaccine even went into clinical trial,” lead researcher Dr. Karen L. Kotloff told Reuters Health. “The surface-expressed M protein, a major protective antigen of GAS, was always the focus of these efforts.”
However, serologic cross-reactivity between M protein epitopes and human tissue and increased rates of rheumatic fever among vaccinees brought clinical testing to a halt.
“What enabled this trial to go forward is that very detailed studies of M protein made it possible to tease out areas of the protein thought to be involved in stimulating protective immunity from those involved in stimulating an autoimmune response,” Dr. Kotloff added. “The ability to separate these areas gave scientists the confidence that we could again begin clinical testing of GAS vaccine.”
Dr. Kotloff, at the University of Maryland School of Medicine in Baltimore, and associates constructed a recombinant fusion peptide GAS vaccine containing N-terminal M protein fragments from six strains associated with pharyngitis and rheumatic fever.
They tested the vaccine in 28 healthy adult volunteers ages 18 to 50. Each volunteer was treated with three spaced intramuscular injections of vaccine into the deltoid muscle of alternating arms, then underwent one year of intensive follow-up.
Vaccination was well tolerated with local reactions graded as mild or moderate. There were no cases of unexplained or persistent fever, or of sequelae associated with GAS infection, the authors note, and no evidence of tissue cross-reactive antibodies.
The highest dose elicited increases in functional antibody levels to all six component M antigens. The team also demonstrated that sera from the vaccinees, when incubated with cultured streptococci, were more bactericidal than sera collected prior to vaccination.
“At this preliminary stage this was very promising news, suggesting that additional development of this concept is warranted,” Dr. Kotloff continued. “As a next step, a vaccine was made including 26 types of GAS believed to include 80% to 90% of the important types in this country. That vaccine is now in clinical trial in Canada.”
In his editorial, Dr. Pichichero, at the University of Rochester Medical Center in New York, comments that “the regulatory challenges for GAS vaccines are substantial.” The need to rule out rare adverse events will require prelicensure trials involving up to 60,000 subjects.
Nevertheless, he maintains, the report by Dr. Kotloff’s group “is a positive step in a long journey ahead to develop a GAS vaccine.”
Source: JAMA 2004;292:709-715. [ Google search on this article ]
MeSH Headings:Recombinant Proteins: Vaccines, Synthetic: Vaccines, DNACopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
