Development of the Candidate Tuberculosis Vaccine H56:IC31 Ended Based on Early Data from the Prevention of Recurrence (POR) TB Consortium

COPENHAGEN (19 December 2023)—The first analyses of data from the Phase 2b vaccine trial A-055 show that the tuberculosis (TB) vaccine candidate, H56:IC31, was well tolerated and demonstrated an immune response compared to the placebo in participants, all of whom had previously had TB. However, the primary analysis showed it did not provide protection against TB recurrence, reported Statens Serum Institut (SSI), IAVI and trial partners who are part of the Prevention of Recurrence (POR) TB Consortium today. Based on these trial data, SSI has stopped development of the vaccine.

A supporting analysis points in the direction of an increased rate of TB recurrence among people who received the study vaccine (5.8%) compared to people who received the placebo (3.4%), although this cannot be concluded with certainty. Analyses are ongoing, including to understand whether people in one group were, by chance, more likely to get recurrent TB even before the vaccination.

Out of 806 participants who contributed to the primary analysis, 37 participants developed TB recurrence. Of these, 14 out of 406 (3.4 %) had received the placebo and 23 out of 400 (5.8 %) received the H56:IC31 vaccine candidate. All participants had previously had TB, and the difference of recurrent cases between H56:IC31 and the placebo was primarily due to relapse of the original infection rather than new infection with a different TB strain.

“The continued health and safety of participants is the first priority of the partners ,” said Rasmus Skaarup Mortensen, head of TB vaccine research at SSI. “Participants in both the vaccine and placebo group are being informed and encouraged to visit their health clinics for further explanation of study results and reminded to seek medical help and treatment in the event that they experience signs or symptoms suggesting a relapse of TB.”

“We are, of course, disappointed with the results but are committed to learn from this trial,” continued Mortensen. “This includes a detailed analysis of the clinical trial samples as well as an in-depth review of the preclinical and clinical data. We will share our results and full analyses with the field.”

The trial ran from 2019-2023 in South Africa and Tanzania and had a total of 831 participants across six sites. All vaccinations in this trial were completed as of 18 March 2022, and monitoring of participants continued until 23 March 2023, as specified in the trial protocol. The trial was approved by national regulatory authorities in South Africa and Tanzania, independent ethic committees at each trial site, and local community advisory boards.

“Our primary focus is now to reach all the participants and remind them about TB recurrence,” said Mark Hatherill, Director of the South African Tuberculosis Vaccine Initiative (SATVI) and Principal Investigator of the trial in South Africa. “Based on what we know about TB recurrence, most of the risk is in the first two years after TB disease. The majority of participants completed their TB treatment more than two years ago, but all participants are being contacted in case they subsequently developed symptoms of possible relapse that would need a repeat course of treatment.

“TB is treatable, yet 1.3 million people die from TB each year – and a quarter of these deaths are in Africa,” said Issa Sabi, research scientist at the National Institute for Medical Research (NIMR) in Tanzania and Principal Investigator for the trial in Tanzania. “Multidrug-resistant TB is a growing problem. There is an urgent need for a safe and effective vaccine.”

People who had TB once are at a higher risk of developing recurrent cases of TB. This trial was designed to determine whether the TB vaccine candidate, called H56:IC31, was safe and could protect this patient population from a recurrence of TB disease. The availability of a vaccine that prevents recurrence of TB would be a significant advance in the control of TB.

“This was a well-conducted study,” said Pauline Beattie, Operations Manager and Scientific Advisor at the European & Developing Countries Clinical Trial Partnership (EDCTP), which provided the funding for this trial. “These results will inform decisions about the development of future TB vaccines.”

“It’s important to note that using a vaccine to prevent recurrent TB in people who have recovered from active TB is a high bar,” said Lewis Schrager, senior leader of TB vaccine development efforts at IAVI. “It remains essential to continue efforts to develop TB vaccines designed to prevent TB disease from developing in the first place. With more than 10 million people a year falling ill from TB, the need for effective vaccines to prevent TB disease is urgent.”

During the trial, participants were closely monitored for signs of TB disease. If participants presented with clinical suspicion of TB, laboratory tests to confirm TB disease were conducted. If confirmed, participants were referred to TB treatment management as per national program guidelines.

“Like all vaccines entering Phase 2 trials, this vaccine demonstrated safety and an immune response before proceeding to Phase 2,” said Mortensen of SSI. “Specifically, H56:IC31 demonstrated an acceptable safety profile and was immunogenic in four previous clinical trials in a total of 164 humans prior to A-055.”

H56:IC31 is a multistage vaccine developed by SSI comprising a fusion protein of Mycobacterium tuberculosis (Mtb) antigens (Ag85B, ESAT 6, and Rv2660c) combined with the adjuvant IC31® developed by Valneva and licensed to SSI. It was developed as a preventive vaccine against TB disease, and as a therapeutic vaccine when used in combination with anti-TB drugs or to reduce the recurrence rate when administered following successful treatment of Mtb infection.

“We have stopped the development of this vaccine candidate, but our commitment to finding safe and effective vaccines continues,” said Mortensen. “Efforts will move forward with other promising vaccine candidates.” This includes H107e/CAF10b, being developed by SSI, which is focusing on preventing TB from occurring in healthy people with no history of the disease.

The trial was a collaboration between Statens Serum Institut, the product developer; IAVI South Africa, the trial co-sponsor; and a number of other partners.

The POR TB Consortium is part of the EDCTP2 Programme supported by the European Union. Read more about The POR TB Consortium