MVA85A Tuberculosis Vaccine Prime and Selective Delayed BCG Boost in Infants of HIV Infected Mothers

Lead Research Organisation: University of Cape Town
Department Name: Health Sciences Faculty

Abstract

BCG vaccine offers limited protection against lung TB in children. BCG vaccination is safe for most newborn babies, but may cause severe, often fatal, complications in babies with HIV infection, even with antiretroviral treatment (ART). The WHO recommends that BCG should not be given to babies known to be HIV infected. However, HIV testing is not accurate until 6 weeks of age, when BCG has already been given at birth. More than one quarter of South African babies were born to HIV infected mothers in 2009.

South Africa has the highest annual TB rate in the world and children of HIV infected mothers are at especially high risk of TB. New TB vaccines are being developed and tested (http://www.stoptb.org/wg/new_vaccines/). MVA85A is a new TB vaccine, similar to the smallpox vaccine, but with a TB protein added. MVA85A vaccine has been shown to be safe and generates an immune response against TB in children and adults, including people with HIV infection.

We have shown that if BCG vaccination is delayed for several weeks after birth, the immune response thought to be important for protection against TB is improved. Immunity is also improved if a new TB vaccine, such as MVA85A, is given several weeks after BCG. Some studies suggest that it does not matter for immunity whether BCG or the new vaccine is given first. We will test whether MVA85A vaccine can be given to babies at birth, at our experienced TB vaccine trial sites near Cape Town, South Africa, where rates of HIV infection and TB are high.

This trial will test the safety and immunity of MVA85A vaccination at birth, compared to a dummy vaccination (placebo), in 340 babies of HIV infected mothers, followed up for one year. Only those babies proven not to have HIV infection would receive delayed BCG vaccine at 8 weeks of age. HIV infected babies would benefit by not receiving BCG and this is the reason for testing newborn MVA85A vaccination among infants of HIV infected mothers. If we show that newborn MVA85A vaccination has few side-effects and generates a good immune response against TB, we may proceed to test whether this new TB vaccine strategy actually prevents TB, among all infants, regardless of maternal HIV infection. These findings will be critically important for vaccine safety, and prevention of childhood TB, and may lead to key improvements in the global infant vaccination schedule.

Technical Summary

Bacille Calmette Guerin (BCG) vaccine protects against childhood disseminated tuberculosis (TB) and meningitis, but efficacy against pulmonary TB is inconsistent. Administration of live attenuated BCG to known HIV infected infants is contraindicated by the World Health Organization (WHO), due to risk of disseminated BCG disease. BCG disease causes considerable morbidity, may be fatal, and may manifest as immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment (ART). Developing countries, which lack capacity for integration of early HIV testing with infant vaccination schedules, have not implemented the WHO guidelines. Babies of HIV infected mothers, who constituted 29% of all babies born in South Africa in 2009, would benefit from a new TB vaccine regimen that delays BCG until after HIV infection has been excluded.

We have shown in humans that delaying BCG vaccination until 10 weeks of age results in more optimal T cell immune responses. Animal studies suggest that the prime and boost sequence of BCG and new TB vaccines (heterologous prime and boost) is not critical for development of optimal immunity. One new vaccine, MVA85A, a non-replicating Vaccinia virus expressing M.tuberculosis antigen 85A, has been tested as a TB vaccine boost among infants, children and adults. We will build on a long-standing relationship with the vaccine developers, Oxford University and Emergent Biosolutions, to test whether MVA85A can be given as the priming TB vaccine at birth. Exceptional research capacity and immunology laboratory infrastructure has been established to conduct quality-assured TB vaccine trials at our trial sites near Cape Town, South Africa. This randomised controlled trial will test safety (local, regional, and systemic adverse events) and immunogenicity (serial measurements of CD4/CD8 T cell intracellular cytokine production, cytotoxic and proliferative potential) of MVA85A prime vaccination compared to placebo, in 340 newborns of HIV infected mothers, followed at 8 weeks by selective BCG boost, given only to infants confirmed HIV uninfected by PCR.

The safety benefit gained by withholding BCG vaccination from HIV infected infants is the rationale for testing MVA85A prime among newborn infants of HIV infected mothers. The precedent safety and immunogenicity data from this strategically important trial will establish the equipoise to fast-track efficacy trials of this novel TB vaccine regimen among all infants, regardless of maternal HIV infection. The findings, which are of global health importance for vaccine safety, and TB control, among HIV exposed children, may lead to key improvements in the routine infant vaccination schedule.

Publications

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Description IDRI Collaboration 
Organisation Infectious Disease Research Institute (IDRI)
Country United States 
Sector Charity/Non Profit 
PI Contribution Successful co-applicants in a Wellcome Trust application to support a TB vaccine trial for prevention of recurrent TB disease
Collaborator Contribution Successful co-applicants in a Wellcome Trust application to support a TB vaccine trial for prevention of recurrent TB disease
Impact None as yet
Start Year 2013
 
Description NIH NIAID Planning Grant Application 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution Grant co-investigators Hatherill, McShane, Scriba, Walzl, and Hesseling have since collaborated on an NIH NIAID clinical trial planning grant application to support a trial of safety and immunogenicity of MVA85A vaccine given for prevention of recurrent TB disease.
Collaborator Contribution Grant co-investigators Hatherill, McShane, Scriba, Walzl, and Hesseling have since collaborated on an NIH NIAID clinical trial planning grant application to support a trial of safety and immunogenicity of MVA85A vaccine given for prevention of recurrent TB disease.
Impact Outcome awaited.
Start Year 2012
 
Description TB Diagnostic Collaboration 
Organisation University of Washington
Country United States 
Sector Academic/University 
PI Contribution Proof of concept buccal swab M. tuberculosis PCR study, with another NIH grant application pending, in collaboration with Prof. Gerard Cangelosi, University of Washington, Seattle.
Collaborator Contribution Laboratory and assay expertise.
Impact Manuscript submitted Scientific Reports.
Start Year 2013
 
Title MVA85A candidate tuberculosis vaccine 
Description Phase II Randomised Controlled Trial to Evaluate Safety and Immunogenicity of MVA85A and Selective, Delayed Bacille Calmette-Guerin (BCG) Vaccination in Infants of HIV Infected Mothers Recruitment completed, follow-up is ongoing. Estimated date of completion is May 2015. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact Clinica trial is ongoing 
 
Description Beat TB Street Theatre Project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 2nd Wellcome Trust award to Dr Michele Tameris for community engagement in TB research
Year(s) Of Engagement Activity 2015,2016
 
Description TB Vaccine Drama 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact The drama production toured schools in the study site area to increase awareness of TB, TB vaccines, and participation in trials

Impact on study recruitment to be assessed in 2013
Year(s) Of Engagement Activity 2013
 
Description Wellcome Trust funded Community Engagement grant (Dr Michele Tameris) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Community education about TB research using media, including drama

Planning stages
Year(s) Of Engagement Activity 2014