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Investigational TB vaccine lacks efficacy in infants
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An investigational tuberculosis vaccine was found to be well tolerated and modestly immunogenic but unable to confer significant protection against tuberculosis or Mycobacterium tuberculosis infection in infants, according to findings released today in The Lancet.
The vaccine, modified vaccinia Ankara virus expressing antigen 85A (MVA85A), was developed as a heterologous boost for the bacillus Calmette-Guérin (BCG) vaccine and showed early promise in stimulating high levels of immune response in adults. However, results from the first efficacy trial in infants indicate these results were not replicated.
Helen McShane
“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,” Helen McShane, BSc, MRCP, PhD, who developed the vaccine and is a professor of vaccinology, The Jenner Institute, University of Oxford, said in a press release. “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. This is the first efficacy trial of a new TB vaccine since BCG, a significant step in itself, and there is much that we and others can learn from the study and the data it has produced.”
The randomized phase 2 trial was designed to further assess the safety, immune response and efficacy of MVA85A in TB disease prevention in children. The trial was conducted in South Africa and enrolled 2,794 healthy infants aged 4 to 6 months who received BCG vaccine. The infants were randomly assigned to receive MVA85A (n=1,399) or placebo (n=1,395); the children were followed for up to 37 months.
The researchers found 39 cases of TB in the placebo group and 32 in the MVA85A group, demonstrating a nonsignificant vaccine efficacy of 17.3%.
MVA85A was generally well tolerated, with similar rates of serious adverse events reported in both groups (18% placebo vs. 18% vaccine), but none were deemed to be vaccine related. Respiratory and gastrointestinal infections were the most commonly reported serious adverse events.
The study researchers said, “The reasons for the absence of MVA85A efficacy against TB or M. tuberculosis infection in infants need exploration.”
Christopher Dye, FMedSci, FRS, director of health information in the Office of HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases at WHO, and Paul Fine, AB, VMD, MSc, PhD, of London School of Hygiene and Tropical Medicine, wrote in an accompanying commentary that these findings should not be considered a “terminal prognosis” for MVA85A.
Dye and Fine said many questions have yet to be answered, including: 1) could MVA85A be effective against infant and childhood TB when used independently of BCG?; 2) considering the variable performance of BCG in different populations, can it be assumed that the same results will be obtained with MVA85A in other populations?; 3) could MVA85A, working as a booster to BCG, protect adolescents and adults against pulmonary TB in a way that it cannot protect infants?; and 4) might this vaccine work if administered to patients with HIV?
“Now is a key moment in TB vaccine research. Trials such as that of Tameris and colleagues are at last generating hard evidence about protection against TB in human beings, the most important goal of immunization,” Dye and Fine wrote. “If the history of TB vaccine research teaches us anything, it is to expect surprises. We need to go on playing the high-stakes game.”
Disclosure: Aeras, a nonprofit product development organization, was the trial sponsor. Aeras and the Oxford-Emergent Tuberculosis Consortium (OETC) contributed to study design, data interpretation and writing of the manuscript. McShane is a shareholder in OETC, which is a joint venture between Emergent BioSolutions and the University of Oxford.
Perspective
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Jeffrey R. Starke, MD
The “Holy Grail” for TB control, especially in high burden resource-challenged countries, is an effective vaccine. While the BCG vaccines reduce the incidence of life-threatening forms of TB [meningitis and disseminated disease] in infants and young children, they have much less effect on preventing pulmonary TB and infection with Mycobacterium tuberculosis.
In this trial, MVA85A vaccine — a modified recombinant strain of Vaccinia Ankara virus that expresses the immunodominant M. tuberculosis protein 85A — was given to infants who had received the local BCG vaccine at or near birth. The rates of life-threatening TB were low in both the study and placebo groups, likely due to the BCG vaccine. However, the BCG vaccine used in this area has not worked well in this population of infants in preventing pulmonary TB, and equally high rates were seen in both groups. That the vaccine was not very effective compared with placebo is not surprising.
The trial was conducted in an area of hyperendemic TB with annual case rates of 1,000 to 3,000 cases per 100,000 population per year. In addition, many of the current TB vaccine candidates appear to have FIVE to 10 times the immunogenicity in adults that they do in infants. However, there are two critically important positive outcomes of this trial. First, was the demonstration that a TB vaccine field trial among infants could be conducted in a safe and scientifically valid way. The endpoint measurements in this trial were generally more specific and rigorous than in the previous BCG trials, and cohort retention in the trial was very high. Second, the vaccine was shown to be quite safe, with no serious adverse events linked directly to the vaccine. While this trial did not provide “the answer” to TB vaccinology, it is a crucial initial step in the, hopefully, inexorable march toward vaccine-driven elimination of tuberculosis in the world.
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