Tuberculosis vaccine

Abstract

Global burden of tuberculosis is nearly 12 million. As per the WHO Global TB Report 2013, there were an estimated 8.6 million incident cases of TB globally in 2012. Tuberculosis is an issue that affects development through its effect on the health of individuals and families. In humans, neither prior latent infection nor recovery from active TB confers reliable protection against reinfection or reactivation disease. The power of vaccines as a public health intervention lies in their ability to reduce onward transmission of disease as much as in their ability to protect vaccinated individuals; a feature generally referred to as “herd immunity.” MVA85A is a booster vaccine, used in con-junction with BCG as part of a prime-boost strategy. BCG serves as the prime vaccination and MVA85A as the boost, operating under the theory that the addition of MVA85A will produce a better immune response and more protection against TB than BCG vaccination alone. There is a critical need to raise the profile of TB vaccine research at the community, national, regional, and global levels in order to generate support and political will, increase investment, create an enabling and supportive environment for clinical trials, and lay the groundwork for acceptance and adoption of new TB vaccines once licensed.

Introduction and Problem Statement

Tuberculosis, Some people know the name, without knowing much about the illness itself. Tuberculosis (TB), a threat to mankind with huge burden is still a neglected cause of death and disability in most of the developing countries. This preventable deadly disease has a limited political backing and little interest from the private sector. TB neglect is partly because the greatest burden of disease is among those who are economically deprived and socially excluded. Until the early 1990s, there was a firm belief that tuberculosis had been conquered (at least in the economically developed world), and that the disease no longer justified priority status, but the reality is quite different i.e., far from truth.

Global burden of tuberculosis is nearly 12 million. As per the WHO Global TB Report 2013, there were an estimated 8.6 million incident cases of TB globally in 2012 with 1.3 million deaths due to this disease (including 320 000 deaths among HIV-positive people).¹

In 2006, WHO launched Stop TB Strategy. The core of this strategy is DOTS, the TB control approach launched by WHO in 1995. Major targets under this are to reduce the prevalence of TB and death rates by 50% relative to 1990 by 2015 with the ultimate target of eliminating TB as a public health problem i.e., 1 case per million population by 2050.²

Despite the inclusion of tuberculosis in the Millennium Development Goals (MDGs), tackling this infection as a wider development problem has hardly begun. One difficulty is that the central development issue for tuberculosis is its complex intersection with poverty. Tuberculosis is an issue that affects development through its effect on the health of individuals and families. In humans, neither prior latent infection nor recovery from active TB confers reliable protection against reinfection or reactivation disease.³

Need for Vaccine

Vaccination is one of the most cost-effective public health interventions, yet the only available vaccine against TB, Bacille Calmette-Guérin (BCG), provides very limited protection against pulmonary TB, the most prevalent and contagious form of the disease.

Knowledge gaps exist in understanding the mechanisms of natural protective immunity and immunopathogenesis, as well as vaccine induced protective mechanisms.^4-6 Protective efficacy is notoriously variable depending on the population that is targeted by M. bovis BCG vaccination.

An alternative perspective to explain the interaction of the host with the M. tuberculosis pathogen is that modern humans may have co-evolved with M. tuberculosis in the form of a relatively benign infection, with the current aggressive disease manifestations emerging as a consequence of recent increases in human population densities. It may be that our natural immune response is programmed to treat M. tuberculosis as a commensal organism requiring containment rather than elimination.⁷

The power of vaccines as a public health intervention lies in their ability to reduce onward transmission of disease as much as in their ability to protect vaccinated individuals; a feature generally referred to as “herd immunity.” While BCG clearly provides a degree of protection to individuals, saving the lives of around 50 thousand children every year, wider public health benefit has been precluded by the absence of any measurable impact on TB transmission.

While current clinical trials of new TB vaccines focus specifically on the primary endpoint of a reduction in disease incidence between vaccinated and unvaccinated individuals, it may also be useful to consider the potential design of trials with transmission endpoints. There has been a tremendous progress in TB vaccine development over the past decade. Sixteen candidates have advanced to clinical trials and 12 are currently being tested in the field.⁸

The discovery of biomarkers and correlates of immunity for TB could greatly simplify the development and evaluation of new TB vaccines. Biomarkers that signal vaccine efficacy would help guide the selection of the most promising vaccine candidates much earlier in the development process, saving time, money and resources. Biomarkers and correlates that predict what vaccines will be most effective would significantly reduce the number of participants needed for clinical trials (currently estimated at tens of thousands for a Phase III licensure trial) and decrease the timelines and costs of these trials (Table 1).

Table 1. Global TB Vaccine Pipeline 2013 Stop TB Partnership⁹.

Name of the Vaccine	Phase of Clinical Trial
AdAg85A	Ӏ
MTBVAC	Ӏ
ID93+GLA-SE	Ӏ
VPM 1002	II
H1+IC31	II
RUTI	II
H56/AERAS-456 +IC31	II
H4/AERAS-404 +IC31	II
Ad35/AERAS-402	II
MVA85A/AERAS-485	II b
M72+AS01	II b
M. Vaccae	III

Majority of these activities were focused on the strategic goal of rapidly generating human protection data but they primarily included two constrained sets of activities. First, because there was no rational reason to prioritize one candidate over another, the vaccine candidates were selected to move into humans primarily based on which were furthest along in the preclinical development process. Second, clinical vaccine testing capacity was developed at centers selected for relatively high rates of TB in populations that were felt to be the most easily studied.¹⁰

While current clinical trials of new TB vaccines focus specifically on the primary endpoint of a reduction in disease incidence between vaccinated and unvaccinated individuals, it may also be useful to consider the potential design of trials with transmission endpoints.

MVA85A Vaccine: Basis of Future Prospect

MVA85A is a novel TB vaccine candidate originally developed by the University of Oxford with funding from the Wellcome Trust. MVA85A is a booster vaccine, used in conjunction with BCG as part of a prime-boost strategy. BCG serves as the prime vaccination and MVA85A as the boost, operating under the theory that the addition of MVA85A will produce a better immune response and more protection against TB than BCG vaccination alone (Box 1).

Box 1. TB Vaccine Types

Viral-vectored: MVA85A, AERAS-402, AdAg85A

Protein/adjuvant: M72, Hybrid-1, Hyvac 4, H56, ID93

rBCG: VPM 1002

Killed WC or Extract: Mw, RUTI

The results from this trial, involving 2797 HIV-negative infants previously vaccinated with BCG, show that MVA85A met the primary objective of safety. However, differences between the rates of TB in infants vaccinated with MVA85A and in the placebo group were not statistically significant, indicating that MVA85A was not effective at preventing TB in BCG-vaccinated infants.

Still our knowledge about the interaction between Mycobacterium tuberculosis and the human immune system is incomplete and is hampering progress in this field. Thus new TB vaccines are need of the hour. TB remains humanity’s second deadliest infectious disease. New vaccines that prevent adolescents and adults from developing tuberculosis disease would be the single greatest advance in the global fight against the scourge which has been plaguing mankind for decades.

Conclusion

Getting the first new TB vaccine expeditiously into the hands of health care workers can be accomplished only through continued and close collaboration among all stakeholders. There is a need for renewed, intensified and well-integrated international effort to develop more effective TB vaccines, quickly and cost-effectively as possible to maximize limited resources.

There is a critical need to raise the profile of TB vaccine research at the community, national, regional, and global levels in order to generate support and political will, increase investment, create an enabling and supportive environment for clinical trials, and lay the groundwork for acceptance and adoption of new TB vaccines once licensed. To accomplish this, advocacy, communications and resource mobilization must be prioritized.

Completion of the MVA85A trial has increased scientific understanding and will provide crucial information to support areas and partners to develop these other vaccine candidates and to strength the ability to advance the entire TB vaccine portfolio.

10.4161/hv.27108