Tallying the TB vaccines in Clinical Trials
By Richard Jefferys, with the assistance of Claire Wingfield, Eleonora Jimenez and Javid Syed.
7/1/2011 - The relatively small community of researchers, policymakers and advocates involved in the search for an effective TB vaccine met in Tallinn, Estonia in September, 2010 to assess the state of the field and discuss the path forward. The sense of urgency driving this research has recently been underscored in the new Global Plan to Stop TB 2011-2015, which explicitly states that without a new vaccine effective against all forms of TB, the goal of eliminating TB as a public health threat by 2050 will not be met. As described by Claire Wingfield in TAG’s annual pipeline report, TB vaccine development has long languished despite the desperate global need, but there are now encouraging signs of progress. On the second day of the Global TB Vaccines Forum, researchers offered summaries of where their candidates stand on the developmental pathway.
Helen McShane from the Jenner Institute in Oxford described the long road traveled toward efficacy trials by MVA.85A, a modified vaccinia Ankara strain (MVA) vector that carries a single TB antigen (85A, which is abundantly expressed by the mycobacterium and provokes a strong immune response). A total of twelve trials have been completed and four are ongoing, including one phase IIb efficacy trial in infants. A second phase IIb efficacy trial in HIV-positive adults is due to begin next year. The vaccine is being considered as a booster of pre-existing immune responses to 85A, which are present in most people either as a result of BCG vaccination (still widespread because as it offers some protection against non-pulmonary TB in children) or natural exposure to TB.
The phase I and II studies of safety and vaccine-induced immune responses (immunogenicity) have involved 80 HIV-positive people (both on and off ART), 47 people with latent TB infection, 24 children and 1,056 infants. McShane reported that the vaccine has been well tolerated with no serious adverse events. A trial in infants being given the vaccines recommended in the World Health Organization’s Expanded Programme on Immunization (EPI) showed no negative impact from the MVA.85A vaccine. However, the EPI vaccines did slightly reduce the immunogenicity of MVA.85A, which McShane suggested was due to alum adjuvants biasing the immune response to an antibody-invoking Th2 profile and away from the cellular Th1 response favored by MVA.85A.
The studies in HIV-positive people found no difference in the safety profile compared to HIV-negatives, and there were no significant changes in CD4 counts or viral load caused by vaccination. In collaboration with the Vaccine Research Center (VRC) at the National Institutes of Health, the impact of the vaccine on numbers of CCR5-expressing CD4 T cells was evaluated, but again no significant changes were observed. The researchers at VRC also found that 85A-specific CD4 T cells did not contain more HIV DNA than CMV-specific CD4 T cells (which their prior studies have shown to be a relatively resistant population). Not surprisingly, the immunogenicity of the vaccine was better in people whose viral load was suppressed by ART.
McShane noted that the overall immunogenicity data supported advancing the MVA.85A into efficacy trials. Both CD4 and CD8 T cell responses have been induced by the vaccine, with a substantial proportion displaying “polyfunctional” profiles (production of more than cytokine) that have been associated with protection in small animal models.
The target enrollment for the ongoing phase IIb trial in infants is 2,784 (1,392 per arm) and so far 1,673 have been randomized to either MVA.85A or placebo. Protection against both infection and disease will be assessed. Another phase IIb efficacy evaluation in 1,400 HIV-positive adults is due to start in the first quarter of 2011. Sites include Khayelitsha, South Africa and Dakar, Senegal. Both trials are being sponsored by AERAS Global TB Vaccine Foundation. McShane noted that MVA.85A is the most advanced new TB vaccine candidate, and these trials should reveal whether it works.
AERAS-402/Crucell Ad35.TB Vaccine
Up until recently, Jerry Sadoff was head of AERAS but he has now taken the helm of Crucell, a Dutch company with a particular focus on developing adenovirus-based vaccine vectors for infectious diseases. Sadoff is a well-known figure in the field, as he developed many successful vaccines during a previous tenure at Merck & Co., Inc. At the TB vaccines forum, Sadoff gave an update on Crucell’s lead TB vaccine candidate, which uses an attenuated adenovirus serotype 35 (Ad35) as a vector to deliver three TB antigens (85a, 85b and 10.4) in the form of a single fusion protein. The vaccine is a few steps behind MVA.85A on the developmental pathway, it has been studied in around 150 adults and 40 infants in phase I and II trials.
Given after priming with BCG in adults, Ad35.TB has been shown to induce polyfunctional CD4 T cells and high magnitude CD8 T cell responses that primarily make interferon-gamma and/or TNF alpha. In infants, Sadoff reported that the response is more skewed toward CD8 T cells. In a phase II trial in adults being treated for pulmonary TB, in whom CD8 T cells targeting the 85b antigen were generally undetectable, the vaccine successfully induced CD8 T cell responses in the majority of recipients, suggesting it may have potential as an immunotherapy. Sadoff noted that the safety profile has been “acceptable” but did not give details. Ad35.TB is now entering a phase IIb trial in HIV-uninfected infants aged 16-26 weeks; there will initially be a dose-finding period involving infants in Kenya, followed by a planned multicenter safety and efficacy phase that will recruit up to 4,096 infants in Uganda, Kenya, Mozambique and South Africa.
Sadoff also briefly described Crucell’s efforts to streamline and intensify manufacturing of adenovirus vectors. The end result is a new bioreactor with the capacity to produce over 100 million vaccine doses per year.
Statens Serum Institut Subunit TB Vaccines
Søren Hoff from the Statens Serum Institut (SSI) in Denmark reviewed the status of their TB vaccine candidates. The SSI strategy involves protein subunits comprising different TB antigens combined into “fusion molecules.” There are three candidates that are being studied in clinical trials:
- HyVac4: 85b and 10.4 antigens
- Hybrid 1 (H1): 85b and ESAT6 antigens
- Hybrid 56 (H56): 85b, ESAT6 and Rv2660 antigens
Hoff explained that the goal with HyVac4 is to boost existing immunity to BCG, whereas H1 and H56 are undergoing evaluation without regard to BCG or TB infection status. The primary purpose of the ongoing phase I and II trials of these constructs is to evaluate their safety and immunogenicity when combined with different adjuvants (substances that enhance immune responses to co-delivered antigens). This is an issue with protein subunit vaccines because they lack the inherent adjuvant properties of viral vectors like MVA and Ad35. In terms of safety, local reactions such as injection site soreness have been reported, but systemic reactions have been rare and mild. Immunogenicity data are limited but there is evidence of antigen-specific T cell memory persisting out to 2.5 years. H56 has not yet been studied in humans but a trial is being planned; this construct is unusual because it contains an antigen, Rv2660, that was selected because it is expressed during TB latency. The process that led to the selection of Rv2660 was very complex, involving gene expression studies of latent TB and assessment of more than 30 different vaccines in over 4,000 animals. SSI’s work is being supported by AERAS and the Bill & Melinda Gates Foundation. It is anticipated that HyVac4 will be the first candidate to undergo efficacy testing.
GlaxoSmithKline’s TB Vaccine Program
Few large pharmaceutical companies have been willing to try and navigate the complex terrain of TB vaccine development, but GSK is an exception. At the forum, Opokua Ofori-Anyinam gave an update on the status of their TB vaccine program. The lead candidate is a fusion protein named M72 containing two TB antigens, 32a and 39a. The vaccine has been studied with several of GSK’s proprietary adjuvants, with a compound named AS01E eventually selected for further development. Trials so far have included people lacking an immune response to TB (as measured by PPD) in Europe and South Africa, PPD+ adults, adolescents and infants in South Africa, the Philippines and the Gambia, and HIV-positive adults on ART in Switzerland. An additional trial in HIV-positive adults with CD4 counts over 200 who are not on ART is due to take place in India pending regulatory approval. The vaccine has induced robust polyfunctional CD4 T cell responses against the M72 antigen, but no CD8 T cell responses. No serious adverse events have occurred; the main side effects are transient local injection site reactions. Opokua Ofori-Anyinam stated that GSK is now mulling the possibility of efficacy trials.
A much more recent entry into clinical trials is VPM1002, a live TB vaccine made from a genetically modified BCG strain (BCG subtype Prague). The vaccine was originally made by the research group of Stefan Kaufmann at the Max Planck Institute for Infection Biology and is now being developed by Vakzine Projekt Management (VPM) in Germany. Leander Grode from VPM described results from phase I trials involving a total of 80 people. The main side effects have been induration, erythema and swelling at the injection site with no serious events occurring. The vaccine has induced TB-specific CD4 and CD8 T cell responses, in many cases producing two or three cytokines. A 24-person phase Ib trial in South Africa is now evaluating safety, tolerability and immunogenicity healthy adults using standard BCG immunization as a comparator. A phase II trial in neonates is planned to take place next, also in South Africa.
RUTI is a killed TB vaccine that was generated by growing Mycobacterium tuberculosis under stress conditions (low oxygen and low pH). The final product is fragmented, with endotoxin-like products removed, and encased in liposomes (fat molecules). Originally discovered at Institut Germans Trias I Pujol in Badalona, RUTI is now being developed by a Spanish Biotech, Archivel Farma. Luis Ruiz summarized the current status of the vaccine: there has been a phase I study in Spain, and a dose-ranging phase II is ongoing a three sites in South Africa. Results from the phase II are anticipated in early 2011. The development strategy of Archivel Farma is based on the possibility of using the vaccine to accelerate the treatment of latent TB in combination with isoniazid. Ruiz stated that the company is currently collaborating with Gavin Churchyard from the Aurum Institute in South Africa on a phase III “non-inferiority” study that will compare one month of isoniazid plus RUTI to six months of isoniazid plus placebo.
Zhou Xing from McMaster University in Canada presented on the most recent TB vaccine to enter human trials. The construct is an adenovirus serotype 5 vector encoding the 85a antigen, so far 18 people have been immunized in an ongoing phase I trial and Xing was able to share information from 16 of them. Two-thirds have experienced local reactions that in most cases resolved within 24 hours. Using ELISPOT assays to measure 85a-specific T cells, Xing showed that there was a peak at two weeks post-immunization but responses could still be detected after 24 weeks of follow-up. The strategy is to use the vaccine to boost BCG and Xing’s group is particularly interested in pursuing intranasal delivery, because data from their laboratory suggests that the presence of T cell responses in the airways correlates with protection in animal models whereas T cell responses in the lung do not. Xing suggested that measuring vaccine-induced immune responses at mucosal sites and/or evaluating mucosal homing receptors on T cells deserves consideration in TB vaccine development.
The Role of SATVI & EDCTP
Two organizations that play key roles in almost all TB vaccine trials are the South African TB Vaccine Initiative (SATVI) and the European & Developing Countries Clinical Trials Partnership (EDCTP). To some extent, this reveals the relatively limited infrastructure available for the conduct of clinical TB vaccine research. There are some advantages, however; at the Forum Willem Hanekom from SATVI was able to show comparative immunology data obtained in trials of many of the vaccines described above, and the fact that these results were all from the same laboratory greatly increases confidence that the comparisons are meaningful. As these candidates progress into efficacy trials, this should be extremely helpful in the search for immune correlates of protection.
Charles Mgone from EDCTP described the active role they are playing in facilitating TB vaccine research, including establishing “networks of excellence” and a regulators forum. Mgone cited the example of the phase I trial of Statens Serum Institut’s H1 vaccine, which was used as an opportunity to partner an Ethiopian clinical trial site with the Institut Pastuer Madagascar and the KMC hospital in Tanzania, as a means to build knowledge and capacity. The EDCTP has also recently issued a call for applications to study the effect of trial sites on the health and health services of the local community, with the goal of identifying ways to maximize the broader benefits of research. But both SATVI and EDCTP remain under-resourced in comparison to the needs they are attempting to address.
After many years in the doldrums, the search for an effective TB vaccine is finally gaining momentum, with the support of the AERAS Global TB Vaccine Foundation and the Bill & Melinda Gates Foundation playing a very significant role in this shift. The forum in Tallinn was only the second such meeting, which gives a sense of the extent to which the attendees are still Davids facing the Goliath-sized global health threat presented by TB. Results from the current crop of candidates covered in this report will be crucial in determining how the field progresses from here.
Aeras Global TB Vaccine Foundation
European & Developing Countries Clinical Trials Partnership (EDCTP)
GSK Vaccines for the Developing World
The Jenner Institute
South African TB Vaccine Initiative (SATVI)
Statens Serum Institut
Treatment Action Group 2010 Pipeline Report 2nd Edition
Treatment Action Group 2010 Report on Tuberculosis Research Funding trends, 2005-2009