Correlates of Protection

Identification of correlates of protection is of major importance for the development of new effective preventive/therapeutic strategies. Although some progress has been made to identify correlates of protection, much more intensive funding and research are needed to tackle this complex and central area of investigation. Indeed, to date, no convincing correlates of protection have been yet identified for HIV/AIDS, malaria, TB, or NIDs.

As a general assumption, the main correlates of protection in human infections are represented by the presence of pathogen-specific effector cells/molecules (CD8⁺ and CD4⁺ T cells, antibody-producing B cells, neutralising antibodies). More recently, it has become clear that early triggering of innate immune mechanisms can also represent an important determinant of protective immunity. Assays to measure these immune responses are expensive and technically demanding. Therefore, in the search for reliable correlates of protection, priority should be given to the development of simplified, standardised, and low-cost assays.

Mechanisms of Infection and Immunity at Local Sites

The pathogens responsible for HIV/AIDS, TB, and many of the NIDs invade the human hosts at mucosal surfaces, which act as a primary antimicrobial barrier through non-specific and specific defence mechanisms. In most cases, little attention has been focused on the role of local defences in the control of NIDs. Therefore, the design of strategies to target the local immune defences and to elicit an early mucosal immune response will be crucial.

Immunological Memory

Immunity to HIV/AIDS, malaria, TB, and NIDs appears to be short-lived, possibly due to the impairment of memory B and T cells and of long-lived plasma cells.

Only a few well-designed studies in humans are available that detail the effects of co-infection on the immune response, but these indicate that important interactions indeed take place that affect the immune response to each of the infecting organisms. For example, HIV infection in primigravid women significantly reduces antibody responses to several important malaria antigens [8]. It is therefore crucial to understand the effects of multiple infections on adaptive immunity and the establishment of immunological memory to the individual pathogens.

Thus, efforts against HIV/AIDS, malaria, TB, and NIDs should include studies to characterise the profile of the memory responses in naturally exposed populations, as well as development of assays to measure memory phenotype and function.

Impact of Co-Infection on the Outcome of HIV/AIDS, Malaria, TB, and NIDs

More than one billion people worldwide are infected with helminths. Such infections have been shown to cause a range of effects on immune response, characterised by enhanced T helper (Th) 2-type cytokine profile, upregulated regulatory T cell activity, and chronic immune activation. All of these are factors that may have adverse effects on the outcome of subsequent infections and vaccinations. In support of this, studies conducted in animals and humans living in worm-endemic areas have shown that helminths impair resistance against a number of infections, including HIV/AIDS, malaria, and TB [9]–[11]. Accordingly, mortality is high in HIV-positive patients suffering from visceral leishmaniasis, while leprosy seems to be unmasked in co-infected patients when HIV immunosuppression improves with HAART. Infection with schistosomes makes people more susceptible to HIV infection by interfering with immune responses or by increasing the risk of transmission [10],[12]. The interaction between worms and malaria is extremely complex, as people suffering from worm infection and malaria can have higher incidence but reduced severity, while transmission is apparently increased [10],[11]. In sub-Saharan Africa, over 75% of cases of TB are HIV-associated [12]. TB is the leading cause of AIDS-related deaths in low-income countries, and it has been shown that HIV infection increases the risk of progression of TB infection, reactivation of latent infection, and the fatality rate. Other examples of interactions between infections include the interaction between Epstein–Barr virus and malaria, which has been known for many years [13], and HIV and herpes simplex viruses [14]. However, the degree to which this balance is perfected, and the mechanisms by which this is achieved, is far from clear. To understand these complex interactions better, well-designed, controlled intervention studies are needed that could allow us to clarify the mechanisms of protection and to design effective prophylactic and/or therapeutic strategies. Research in this direction is therefore of key importance and should be strongly supported.

Impact of Non-Infectious Agents on the Outcome of HIV/AIDS, Malaria, TB, and NIDs

Infections in poor communities occur in a setting where the population is exposed to several environmental and social conditions that could influence the immune response to pathogens. These include chronic hunger, micronutrient deficiency, multiple pregnancies, etc. Although the relationship between nutrition and immunity is complex, it is clearly established that nutrient deficiencies can severely impair the immune response. Studies in animal models show an association between malnourishment and disseminated disease development after Leishmania infection. However, the complexity of the issue is underlined by the notion that iron deficiency and malnourishment can protect children against severe malaria [15]. Therefore, it becomes essential to investigate and document the basal immunological parameters in a given population, and to determine the “normal values” or reference ranges for the particular population in the endemic set up.

Host Genetics and Outcome of HIV/AIDS, Malaria, TB, and NIDs

The role of genetic differences in the susceptibility of African populations to HIV/AIDS, malaria, TB, and NIDs has not yet been extensively studied. The significance of host genetic background in disease outcome can be exemplified by the well-known protective effect of the sickle cell trait against malaria in Africa. A number of reports have demonstrated the role of chemokine receptor variants in preventing, delaying, or accelerating progression of HIV infection to AIDS [16]. Similarly, host genetic factors such as HLA haplotype and cytokines/receptors gene polymorphisms have been described to influence susceptibility to both TB and malaria. Recently, a polymorphism in the TLR4 gene has been implicated in protection against malaria [17],[18], while a variant of the TLR2-4 adapter Mal/TIRAP can provide protection against invasive pneumococcal infection, malaria, and TB [19]. It will therefore be important to include genetic markers when elucidating the mechanisms of disease.

Novel Adjuvants and Their Modes of Action, and Novel Vaccine Formulations

In view of the fact that reactivity of the immune system can be altered in circumstances of multiple infections, malnutrition, and other conditions, novel vaccine formulations able to stimulate protective immunity in states of altered responsiveness should be considered. The development of safe, potent vaccine adjuvants that enhance and direct vaccine-specific immunity is a crucial issue for all new vaccines for human use. Recent advances in immunological research, especially with regard to innate immunity, has resulted in a number of potent adjuvant candidates that can modulate immune responses in a more controlled and specific manner [20]. However, adjuvants suitable for the developed world might not give the same result in populations already exposed to a number of different NIDs. Thus, development of new adjuvants able to promote broad and sustained immune responses at systemic and mucosal levels still remains a major challenge for vaccinology, especially for people living in developing countries.