Field Notes

• Field Notes

Field Notes

TB Vaccine Researchers Find Strength in Numbers

By Dr. Videlis Nduba

An infectious disease specialist in Worcester, South Africa, frustrated that children were dying from preventable diseases, set up a research unit on tuberculosis (TB) vaccine clinical trials. In Uganda, a doctor who worked on preventing mother-to-child transmission of HIV began working in vaccine research to prevent patients who were living with HIV from dying of TB. I transitioned from sexually-transmitted disease research to working on life-changing vaccines to combat TB.

We are on the front lines of the war against TB, fighting to ensure that vaccine research is conducted to the highest internationally accepted scientific and ethical standards. We share a passion to fight a disease that kills nearly 2 million people each year and sickens more than 9 million.

Together, we principal investigators, along with an expanding cadre of world-class TB vaccine researchers in Africa and Asia, are working tirelessly toward the development of new vaccines that could help stop TB. Through a consortium of TB vaccine researchers around the world called the TB Vaccine Sites Network (TBVACSIN), we share knowledge with one another so that we will be successful in conducting planned multi-center Phase III efficacy trials to license the first new vaccine against TB in 90 years. The sites that we are developing, the clinical trials that we lead, and the expanded infrastructure, professional development, and health care associated with those trials, benefit communities now and have the potential to eliminate tuberculosis forever.

The TBVACSIN Network

The TBVACSIN network allows TB vaccine clinical trial researchers around the world to leverage each others’ knowledge and experience. The network is an ever-expanding informal collaboration between clinical trial sites in Kenya, South Africa, Uganda, Mozambique, Cambodia and India, and hopefully Gambia and Tanzania in the near future. Through conference calls, meetings, and visits to each others’ sites, we share insights, experiences and resources to address the practical aspects of conducting TB vaccine research.

“Experts have complementary skills and can assist each other,” said Dr. Suzanne Verver, senior epidemiologist at the KNCV Tuberculosis Foundation in the Netherlands. “Some sites have more experience in working with schools, and others in statistics, and others in laboratory capacity, and experts from one country can visit other sites to learn more from each other in similar settings.”

TBVACSIN has had an invaluable impact on the work at our respective sites. The network also enhances our ability to obtain funding, such as a grant from the European and Developing Countries Clinical Trials Partnership for a multi-country TB vaccine trial of the vaccine candidate AERAS-402/Crucell Ad 35, which will enable us to fully utilize the power of this network to work collaboratively.

The Tuberculosis Pandemic

Tuberculosis is the second leading infectious disease killer in the world. It is the leading cause of death for people living with HIV in Africa. In most cases, TB is treatable by a cocktail of antibiotics taken for six to nine months. The side effects can be severe - loss of appetite, nausea, vomiting, dizziness, hearing loss. In cases of multi-drug resistant tuberculosis (MDR-TB), TB is resistant to the medicines that doctors usually prescribe and a different regimen is necessary. In a growing number of cases of extensively drug-resistant tuberculosis, the disease may not be treatable at all and is often a death sentence. And many patients die before they even know they have TB.

There are more cases of tuberculosis on the planet than ever before. And despite commendable efforts by the international community to control TB, it would take more than a thousand years to eliminate tuberculosis at the current rate, without the aid of new vaccines, as well as better drugs and diagnostics.

An Outdated Vaccine

The only vaccine licensed to protect against TB, Bacille Calmette-Guérin (BCG), is given to 75 percent of infants worldwide. The vaccine was developed in 1921 by growing bovine tuberculosis on potatoes for 13 years. Unfortunately, it does not reliably protect against adult pulmonary TB, the most common form. Though it has saved some children’s lives by protecting against severe forms of pediatric TB, it has not prevented millions of TB deaths. Nor has it prevented TB from latently infecting 2 billion people worldwide, ready to cause active disease when the immune system is weakened.

Dr. Philippa Musoke, principal investigator for TB Iganga/Mayuge Studies at Makerere University, summed up the problem well: “Despite the current vaccine being given to about 80 percent of the children born in Uganda and the availability of effective drugs for treatment, tuberculosis remains one of the major causes of morbidity and mortality in HIV infected and uninfected adults and children in Uganda.” The same is true here in Kenya, and throughout other countries in Africa and Asia.

Transforming the Global Approach

Since BCG was developed, TB vaccine research has largely been uncharted territory. BCG was developed when TB was endemic in many higher-income countries, like the United States and the United Kingdom. Today, TB is largely a problem of the poor. According to Professor Greg Hussey, director of the South African Tuberculosis Vaccine Initiative (SATVI): “The funding required for TB vaccine research from resource-rich countries of the North has been limited, as TB has historically been a disease of the poorer nations and not a priority for wealthier countries.”

Higher levels of funding for TB vaccine research have become available since the Aeras Global TB Vaccine Foundation - a nonprofit product development partnership funded by the Bill & Melinda Gates Foundation, the government of the Netherlands, and others - was founded in 2003. Aeras works with scientists, academic institutions, industry, foundations, and governments throughout the world to develop new vaccines against TB and ensure that they will be affordable, available, and adopted worldwide.

The goal is to create a TB vaccine regimen that includes a prime vaccine - a recombinant BCG (rBCG) vaccine that will replace the current BCG - to be given at birth and a booster vaccine so that people of all ages remain protected. Researchers develop TB vaccine candidates at laboratories at Aeras, as well as partner with pharmaceutical companies and universities to advance the leading TB vaccine candidates into clinical trials. Aeras already has a manufacturing facility that could produce 200 million bulk doses of a new rBCG vaccine - the estimated world need - and has partnered with manufacturing companies around the world to start producing new TB vaccines at the lowest possible cost and soonest possible date once they have successfully gone through Phase III clinical trials for licensure.

Institutions in many countries have the opportunity to build the capacity to conduct large-scale TB vaccine clinical trials. Since we will need to include tens of thousands of participants in a Phase III trial, and to ensure that new TB vaccines will be effective in a variety of populations, clinical trial sites must be established in many different areas.

Preparing sites requires sufficient laboratory infrastructure, training to conduct clinical trials to the highest ethical and scientific international standards, and educating communities about TB and clinical trials research. Here at Kenya Medical Research Institute/Centers for Disease Control and Prevention, we were fortunate to have extensive experience in running clinical trials, but we needed additional lab equipment, vehicles and staff training to successfully conduct TB vaccine clinical trials. SATVI has the most experience in running TB vaccine clinical trials, with more than 200 staff trained in the complexities of conducting world-class TB vaccine clinical studies and seven TB vaccine studies ongoing there now. My team from Kenya have visited the site in South Africa to learn from their experience, and we have adapted protocols from them and benefited from staff training through a professional development program that covered aspects specific to clinical trials of TB vaccine candidates. At St. John’s Research Institute in India, an office and residential facility was erected for researchers and new laboratory facilities were built.

In our various capacities, we have all witnessed how drastically TB affects our countries and communities. We know this pandemic will continue unless the approach to ending it is transformed. It will take four years and $120 million for a single Phase III trial of one new TB vaccine, and several vaccine candidates may undergo such trials. But together, we share hope that eventually a new vaccine will eliminate tuberculosis forever.

Dr. Videlis Nduba is a primary investigator at the Kenya Medical Research Institute/Centers for Disease Control and Prevention.