Combining two in one: a dual HIV-TB vaccine for vulnerable infants

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  • Professor Kristina De Paris is on a mission to protect infants from infectious diseases. Her group at the University of North Carolina at Chapel Hill is trying to understand critical steps in immune development to improve the design and efficacy of novel paediatric vaccines. A main goal of her group is to develop a paediatric HIV vaccine. In that quest, they have also pursued the development of a paediatric HIV-TB combination vaccine that could target both diseases at once.

    HIV-1 can pass from mother to infant via breastmilk.

    Infants represent one of the most vulnerable populations to infectious diseases. In 2015, the World Health Organization Global Health report stated that 9.6 million people, including 1 million children, suffered from tuberculosis (TB) during 2014. The goal of the De Paris group is to understand why infants are more susceptible to diseases than adults, and how knowledge about immune system development in infants could be used to influence paediatric vaccine design. In particular, the group is interested in paediatric HIV-1 infection resulting from HIV-1 transmission via breastmilk. Although there are now effective antiretroviral therapies to reduce in utero (in the uterus) and intra-partum (during birth) HIV-1 infection, the impact on breastmilk transmission has been more limited. Therefore, an effective HIV-1 vaccine remains a necessary additional measure to prevent paediatric HIV-1 infections.

    The majority of HIV-1 infections in infants caused by ingesting breastmilk occur in sub-Saharan Africa. This region also has a high prevalence of TB infections which are caused by the bacterium Mycobacterium tuberculosis (Mtb).

    Infants represent one of the most vulnerable populations to infectious diseases.

    The currently licensed TB vaccine is the live-attenuated Bacille Calmette-Guérin (BCG) vaccine which was introduced 95 years ago and is still administered to over 80% of new-born infants worldwide. The BCG vaccine protects against the most serious complications associated with TB and has been linked with a significant drop in overall child mortality. It is not, however, effective in adults, and in vaccinated infants immunity decreases over time. However, the BCG vaccine is contra-indicated in HIV-infected infants or infants at risk for HIV infection. This is because these infants have a much higher risk of developing disseminated BCG disease which mimics the symptoms of tuberculosis and can be life-threatening. Therefore, it is vital that a novel paediatric TB vaccine is developed that can protect this vulnerable population.

    Potential interplay between mycobacterial vaccines and HIV infection risk. Infant macaques were immunised during the first week of life with attenuated auxotroph Mtb vaccines or with BCG. Compared to unvaccinated age-matched control infants, monocytes and dendritic cells in blood and tissues of vaccinated animals had enhanced functional responses for several weeks post immunisation. Concurrently, CD4+ T cells also exhibited increased activation, including the upregulation of CCR5, the co-receptor for HIV and SIV. When these animals were subsequently exposed to weekly oral challenges with SIV (to simulate breastmilk transmission of HIV in human infants), more than 80% of vaccinated infant macaques became infected after only two exposures, compared to less than 50% of unvaccinated controls. Whether or not these results are directly translatable to humans remains an unanswered question. The data emphasise the need for larger studies examining interactions between mycobacteria and HIV.

    Combining two in one
    The aim of Professor De Paris’ group, in collaboration with her colleagues at the Albert Einstein Institute in New York, was to develop a paediatric HIV-TB vaccine which would be capable of preventing both oral HIV acquisition and TB infection. Their hypothesis was that a rationally designed strain of human-adapted Mtb may provide better protection than the bovine-adapted BCG. The vaccine proposed comprised an altered Mtb strain which co-expressed HIV antigens. It was intentionally designed to retain the immunogenicity of BCG, but with an improved safety profile. The advantages of the BCG vaccine are threefold: it is known to induce a strong immune response, even in infants without a fully mature immune system; it is effective after just a single dose at birth; and it can be administered orally.

    In previous work, the group established a paediatric rhesus macaque model of oral simian immunodeficiency virus (SIV) infection to simulate breastmilk transmission of HIV in human infants. Using this model, it was demonstrated that an attenuated Mtb strain, which had been engineered to decrease its virulence, could not disseminate in healthy or SIV-infected infant macaques. The modified Mtb was further altered to express SIV antigens. Infant macaques that received an oral Mtb-SIV vaccine to prime the immune system and were boosted intramuscularly with modified vaccinia Ankara (MVA)-SIV developed immune responses to both Mtb and SIV. However, when these vaccinated infant macaques were exposed to a repeated oral SIV challenge, similar to human infants breastfeeding over a period of time, vaccinated animals were more readily infected than the unvaccinated control macaques. This suggested that vaccination with mycobacterium-derived vaccines could potentially increase the risk of HIV infection, rather than reducing it. In areas with a high incidence of TB and HIV, even a small increase in HIV infection rate could increase the overall number of paediatric HIV infections.

    Interestingly, CD4+ T-cells in the vaccinated macaques exhibited signs of persistent activation. Activated CD4+ T-cells are the target cells for HIV-1. Therefore, this persistent activation may prove detrimental in areas with high prevalence of HIV-1. At the same time, this might prove advantageous in inducing immune responses against other pathogens. This phenomenon has been reported in previous studies, including one which looked at risk of HIV-1 infection in South African infants following BCG vaccination.

    The ultimate aim of Professor De Paris’ group is to develop a paediatric HIV-TB vaccine which will be capable of preventing both oral HIV acquisition and TB infection.

    Vaccination is often carried out via injection. However, the BCG vaccine can be administered orally which has many advantages when vaccinating infants.

    In a follow-up study, Professor De Paris and collaborators used archived samples from the study discussed above and, in addition, included a group of BCG vaccinated animals. They examined the responses of infant macaques vaccinated with BCG or the attenuated Mtb vaccine. Although immune activation was more pronounced in the BCG vaccinated animals, both groups showed enhanced responses in certain blood cells; specifically, monocytes/macrophages that harbour mycobacteria (of the vaccine), and the CD4+ T cells that are the targets of HIV-1. Laboratory studies by another research group provided further evidence that exposure of human CD4+ T-cells to Mtb can enhance HIV-1 infection. The mechanisms by which this occurs are not yet clear but may be associated with a group of Mtb-derived molecules that interact with molecules on the immune cell surface, called Toll-like receptors.

    Trained immunity
    It was hypothesised that the activation of CD4+ T-cells might be related to trained immunity. The term “trained immunity” was originally applied to an observation in BCG-vaccinated adults, where the term referred to the persistence of enhanced responses of monocytes to not only
    mycobacterial antigens, but also other unrelated antigens for several months after vaccination. These findings suggested that mycobacterial vaccines, such as BCG, can provide bystander protection against other pathogens. This phenomenon could explain why infant mortality dropped after the introduction of the BCG vaccine. Interestingly, monocytes/macrophages are part of the innate, rapid immune response system that is generally not associated with memory function, yet, trained immunity could potentially confer resistance to reinfection. Trained immunity is thought to be driven by epigenetic changes. Epigenetic changes are heritable, but reversible, alterations that alter gene expression without altering the DNA sequence itself.

    The current work of Professor De Paris’ group also aims to confirm and further define the molecular mechanisms that may promote the non-specific effects of vaccination with BCG, including epigenetic changes in human infant blood cells after BCG is administered at birth.

    The impact on vaccine design
    Vaccines to prevent HIV and TB infection are vital to protect vulnerable infant populations in resource-poor countries where limited access to therapies means that there are high morbidity and mortality rates associated with these diseases. The adjuvant, or enhancing, effects of mycobacterial vaccines may prove highly beneficial for many paediatric vaccines, because they can enhance immune responses in infants in whom responses are generally reduced compared to adults. However, their potential ability to induce long-lasting activation of the immune system in settings with high HIV-1 incidence should be considered. The studies carried out by Professor De Paris and her team provide new insights into paediatric vaccine design which can be used to inform future therapeutic strategies and increase understanding of the complex interactions between vaccine components and host immune responses.

    Is it realistic to assume we may soon see this HIV-TB vaccine used to vaccinate infants in clinical trials? If so, what are the next steps in moving from an animal to a human model?
    The results emphasise the need to understand the many different factors that impact vaccine development and implementation. Right now, the pursuit of an HIV-TB vaccine appears premature and promising novel HIV and TB vaccines strategies will continue to be explored separately. Concurrently, we should aim to gain a deeper understanding of HIV and TB pathogenesis and the interactions between both pathogens. These insights will then enable us to exploit the beneficial features of mycobacteria, such as trained immunity, without introducing additional risk factors for HIV.

    References

  • Research Objectives
    Professor De Paris’ work has focused on developing an HIV vaccine for infants.

    Funding
    NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

    Collaborators

    • Drs Michelle Larsen, Glenn Fennelly, and William Jacobs at the Albert Einstein Institute in New York are experts in TB pathogenesis and vaccine development. This group developed the attenuated Mtb strains.
    • Dr Koen Van Rompay oversaw all the NHP (nonhuman primate) studies and was instrumental in developing a paediatric HIV infection animal model.

    Bio
    Kristina De Paris pursued her original studies in East Germany where she obtained a BS and MS in Biochemistry with Specialization in Immunology. Eventually, she moved to the US and became involved in HIV research. She obtained a PhD in Immunology from UC Davis. In 2009, she joined the Department of Microbiology and Immunology at the University of North Carolina at Chapel Hill, where she is also active in the Center for AIDS Research (UNC CFAR).

    Contact
    Kristina De Paris
    Associate Professor
    Department of Microbiology & Immunology
    University of North Carolina at Chapel Hill
    Burnett-Womack Bldg., Rm. 9029
    160 Dental Circle, CB #7292
    Chapel Hill, NC 27599-7292
    USA

    E: abelk@med.unc.edu
    T: +1 919 843 9560
    W:

  • Combining two in one: a dual HIV-TB vaccine for vulnerable infants

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