TB or not TB: Is Emergent‘s vaccine the solution?
This article was originally published in Scrip
MVA85A, the leading investigational vaccine against TB, has failed to replicate early promising efficacy seen in adults in a new Phase IIb study in infants published this week in The Lancet. But despite the disappointment, experts say this should not spell the end for the product, and the study should provide useful pointers for planning other trials and vaccination strategies.
Currently, the only available vaccine against TB is still the live attenuated Bacille Calmette-Guerin or BCG vaccine, which was developed 90 years ago and has not been improved upon since. BCG protects against disseminated TB in young children but its protection against pulmonary TB is very variable, especially in endemic countries such as South Africa.
A number of new candidates are in the clinic, but MVA85A is the first novel, preventive TB vaccine candidate since BCG to complete a Phase IIb safety and efficacy study. It is a recombinant strain of the modified Vaccinia Ankara virus expressing the immunodominant Mycobacterium tuberculosis protein antigen 85A, and is being developed as a heterologous booster for BCG by OTEC, the Oxford-Emergent Tuberculosis Consortium, with funding from Aeras and the Wellcome Foundation. Earlier trials have shown the vaccine to be safe and to produce consistently powerful immune responses in adults, thought to be important for protection against TB.
The study in 2,797 South African infants was primarily looking at safety, but efficacy was also assessed in a predefined group who received one dose of vaccine. The BCG-vaccinated infants were aged between four and six months and followed for up to 37 months (median 24.6 months).
The study showed that a single dose of MVA85A was not sufficient to confer significant protection against TB disease or infection in infants who had been vaccinated at birth with BCG. There were 32 cases of TB disease in infants receiving the novel vaccine plus BCG compared with 39 cases in those receiving BCG and placebo, giving a non-significant vaccine efficacy of 17.3% at study completion.
The vaccine also did not provide protection at a statistically significant level from infection with M tuberculosis, a secondary endpoint.
“Despite reaffirming the promising safety profile, the vaccine candidate MVA85A did not offer extra protection against TB in South African infants who had already received the BCG vaccine,” said senior author Helen McShane from the University of Oxford. “The vaccine induced modest immune responses against TB in the infants, but these were much lower than those previously seen in adults, and were insufficient to protect against the disease.”
The researchers concluded that the lack of efficacy “needed explanation”. They added that it was unclear whether “a substantially greater magnitude of response, a response that is qualitatively different, or a completely new immunological response would be necessary for protection.”
Nevertheless, other experts stress that the findings are not a “terminal prognosis” for the vaccine. In an accompanying commentary in the Lancet, Christopher Dye, director of health information in the Office of HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases at WHO and Paul Fine from London School of Hygiene and Tropical Medicine, pointed to a number of areas where questions remain over its potential:
- “could MVA85A be effective against infant and childhood tuberculosis when used independently of BCG?...
- “in view of the variable performance of BCG in different populations, can we assume that the same results will be obtained with MVA85A in other populations?...
- “could MVA85A, working as a booster to BCG, protect adolescents and adults against pulmonary tuberculosis in a way that it cannot protect infants?...
- “might this vaccine work if administered to people infected with HIV?”
Emergent Biosolutions said that further analysis of the data and samples collected will be conducted for information that may be helpful for the development of new vaccine candidates such as blood samples will be used to identify “correlates of risk” biomarkers that can predict whether a child will develop TB disease in the future that may aid the development of new vaccines and contribute to clinical trial design.
Other potential TB vaccines at the Phase II stage include GlaxoSmithKline/Aeras’s GSK-692342; Crucell (Johnson & Johnson)/Aeras’s Ad35 (AERAS-402); Intercell and the Statens Serum Institute’s Ag85B-ESAT-6 plus IC31 TB vaccine; and Aeras/Intercell/Staten Serum Institute/Sanofi’s AERAS-404.