Combined efforts in immunology and vaccinology will lead to effective vaccines againstHIV, tuberculosis and malaria (2014)

Recent developments in the field of vaccination against human immunodeficiency virus (HIV), tuberculosis (TB) and malaria were recently reviewed during a course organized in October 2013 by the Ruggero Ceppellini Advanced School of Immunology under the sponsorship of the European Federation of Immunological Societies, the Bill and Melinda Gates Foundation and the Journal of Internal Medicine. During the course entitled ‘Novel vaccination strategies against the three major killers’, the latest advances in the field of vaccines against HIV, TB and malaria as well as vaccine development in general were presented. Expert scientists working on different aspects of vaccination against these three pathogens and related diseases gathered for this course. According to the latest G-Finder report 1, total funding for HIV/AIDS, TB and malaria in 2011 amounted to approximately US$ 2.12 billion with the largest share of US$ 1.03 billion going to HIV/AIDS, US$ 559 million to malaria and US$ 526 million to TB. In addition, around 57.4% of total HIV/AIDS research and development (R&D) funding was allocated for vaccine R&D and 18.6% for basic research; 18.8% of total R&D funding for TB went towards vaccine research and 26.8% to basic research, and the corresponding proportions for malaria R&D were 24.3% and 28.4%, respectively (Fig. 1). In parallel to this, the largest number of publications was in the field of HIV/AIDS, with almost 25 000 publications on HIV and approximately 11 500 on TB and 6000 on malaria for the 2-year period from 2011–2012 (annual PubMed hits for HIV, TB and malaria, 2011–2012 inclusive). The figure of US$ 2.12 billion seems an enormous sum. However, should this funding yield effective vaccines, an even great return of investment can be expected. Current estimates of annual financial losses for TB alone are in the range of US$ 20–200 billion, which is equivalent to 0.5% of global gross national income 2. Three reviews from experts participating in this course have been written for this issue of Journal of Internal Medicine. In the article entitled ‘HIV antibodies and the vaccine problem’ 3, Francesca Chiodi and Robin A. Weiss review the clinical trials of HIV vaccines that have been conducted so far and provide arguments to dispute the efficacy of vaccines that are currently in the pipeline. The major problems encountered in the development of a vaccine against HIV are discussed, and the authors focus on the lack of induction of neutralizing antibodies in HIV vaccine trials. Thus, the first main challenge is how to elicit persistent T and B cell responses, and the second is how to render accessible the crucial HIV target glycoproteins gp120 and gp41, which are naturally sheltered by carbohydrate moieties from protective antibodies. The authors describe promising results in the field of infection with the simian immunodeficiency virus (SIV), using SIV protein-expressing rhesus cytomegalovirus 4. This approach has elicited SIV-specific and sustained CD8+ T-cell responses. In the article entitled ‘The path of malaria vaccines: challenges and perspectives’ 5, Charles Arama and Marita Troye-Blomberg discuss recent developments in the field of malaria vaccination using whole-organism and subunit malaria vaccines. The major obstacle to achieving protection against malaria is that new vaccination strategies, although promising, elicit poor protective immune responses. Therefore, research is needed to improve vaccine formulations and create more stable delivery systems. The complex replication strategy of the malaria parasite Plasmodium falciparum, involving several organs and in several replicative stages characterized by distinct morphological and antigenic patterns, complicates efforts to develop an effective vaccine against malaria. The article by January Weiner 3rd and Stefan H. E. Kaufmann, entitled ‘Recent advances towards tuberculosis control: vaccines and biomarkers’ 6, provides a comprehensive review of the general principles of protective immunity against Mycobacterium tuberculosis (Mtb), the causative agent of TB, as well as of the currently active research areas of TB immunology. Candidates in the TB vaccine portfolio are discussed. An important focus of this article is the value of biomarkers, which can be used to identify correlates of protection against TB disease to distinguish between dormant and active TB stages and to monitor responses to TB vaccines. Although these reviews focus on the biological context of infection with clearly distinguishable pathogens – a virus, HIV; a bacterium, Mtb; and a parasite, P. falciparum – and on the need to address pathogen specificity when designing a vaccine, common points of reflection are presented. The three pathogens cause chronic infection in humans and therefore vaccines must be administerable to both children and adults to prevent life-long persistent infection accompanied by severe symptoms and the need for continuous medication. Thus, a realistic goal for vaccines against these three pathogens may not be sterilizing immunity; due to difficulties encountered in the development of effective vaccines against these pathogens, a realistic aim could be learning how to protect through vaccination against the development of disease that accompanies these infections. Moreover, the number of individuals co-infected with these pathogens is growing exponentially, especially amongst those co-infected with Mtb and HIV. In this regard, vaccines aimed at controlling disease progression during TB need to take into account the immune-compromised status of individuals with HIV infection. The development of vaccines against HIV, TB and malaria requires further economic investment, to unravel missing knowledge and thus to end the epidemics of these diseases. The field of vaccinology emerged in the late 18th century, when Edward Jenner first successfully developed a rational strategy by vaccinating with cowpox (vaccinia virus) against smallpox. A hundred years later, Paul Ehrlich and Elie Metchnikoff established the discipline of immunology by revealing the role of antibodies and of macrophages in host defence against infectious agents. Combination of the two disciplines, vaccinology and immunology, was first demonstrated when Emil von Behring received the Nobel Prize in1901for his discovery that antiserum can be used for passive vaccination against the toxins diphtheria and tetanus. This was the beginning of what became one of the most cost-efficient practices in medicine, and which has saved hundreds of millions of lives. Indeed it has been estimated that vaccinology saves four million individuals annually. However, this is clearly not the case for HIV/AIDS, TB and malaria, which together are responsible for about four million deaths every year. In the past, vaccinology and immunology developed independently from each other; immunology became mainly an academic endeavour and vaccinology developed mostly by trial and error. However, to develop successful vaccines against HIV/AIDS, TB and malaria, both disciplines are essential to rationally design vaccines based on our increasing knowledge of basic immunology. Stefan H.E. Kaufmann is coinventor of the TB vaccine VPM1002, scientific advisor of Aeras on TB vaccines and of Qiagen on TB biomarkers.