TB vaccine trial in infants yields disappointing results

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Feb 4, 2013 (CIDRAP News) – An eagerly anticipated trial of a tuberculosis (TB) vaccine candidate in South African infants yielded disappointing efficacy results, according to study published today in The Lancet.

The findings provide the first look at the efficacy of a new TB vaccine since the Bacille Calmette-Guerin (BCG), the only existing vaccine and one that was first developed 90 years ago. Used in routine childhood vaccination programs in countries where the TB burden is high, the BCG vaccine protects children from severe forms of TB in their first years of life, but doesn't prevent pulmonary TB, which affects adolescents and adults.

Global health groups hope the development of a better TB vaccine will someday allow the battle against the disease to shift from treatment to prevention. There are about 12 new TB vaccines under development. The vaccine candidate described in today's Lancet study, MVA85A, is based on a modified Vaccinia Ankara virus expressing antigen 85A and is designed to boost the efficacy of BCG in previously vaccinated kids.

An earlier trial of the vaccine in adults suggested that the vaccine was safe and produced a consistent and powerful immune response. Today's trial results demonstrated a good safety profile in the infants.

The study included 2,794 healthy infants aged 4 to 6 months old who had previously received the BCG vaccine. Researchers randomized participants to receive either MVA85A (1,399) or placebo (1,395) and followed the groups for 37 months.

Over the study period, investigators detected 39 cases of TB in the placebo group and 32 in the MVA85A group, for a nonsignificant vaccine efficacy of 17.3%. Efficacy against developing a Mycobacterium tuberculosis infection was –3.8%.

The new TB vaccine appeared to be well tolerated. The number of serious adverse events was similar in both groups: 18% in babies who received placebo and 18% in those who received the vaccine candidate, according to the study. The most common adverse events were respiratory and gastrointestinal infections.

Helen McShane, MD, PhD, from the University of Oxford, who developed the new vaccine, said in a Lancet press release e-mailed to journalists, that the vaccine produced a modest immune response against TB in infants, "but these were much lower than those previously seen in adults, and were insufficient to protect against the disease."

She added that the first efficacy trial of a new TB vaccine is a big step in itself and that the findings yielded much valuable information for the team that conducted the study and other vaccine groups, as well.

In the study the authors wrote that although the trial was conducted in infants, they aren't the group responsible for most M tuberculosis transmission and that MVA85A might protect adolescents or adults against pulmonary TB. "MVA85A could also potentially have high efficacy in people of all ages against severe forms of tuberculosis, including pulmonary tuberculosis, without preventing infection or mild forms of disease," they noted.

In an editorial that accompanied the study, two TB experts wrote that although the disappointing findings present a serious challenge to the scientific community, they "are not a terminal prognosis for MVA85A, or for any of the other tuberculosis vaccines in development."

The authors are Christopher Dye, DPhil, with the Office of HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases at the World Health Organization, and Paul Fine, DVM, MSc, PhD, from the Department of Infectious Disease Epidemiology at the London School of Hygiene and Tropical Medicine.

They wrote that the trial was designed to answer only one of a series of key questions about new TB vaccines, and before drawing any firm conclusions from this study, several other questions need to be answered. For example, Dye and Fine said it's not known if MVA85A would be effective against childhood TB when used without BCG.

Also, they wondered how the efficacy of MVA85A would compare with other vaccine candidates that are in phase 2b trials. The two noted that researchers are awaiting the efficacy results of two other subunit boosting vaccines in South African populations, one in infants and one in adults.

Dye and Fine praised the hard evidence that comes from the new findings. "If the history of tuberculosis vaccine research teaches us anything, it is to expect surprises. We need to go on playing the high-stakes game," they wrote.

Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomized, placebo-controlled phase 2b trial. Lancet 2013 Feb 4 [Abstract]

Dye C, Fine PEM. A major event for new tuberculosis vaccines. (Editorial) Lancet 2013 Feb 4 [Extract]

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