KC Jambo, Malawi College of Medicine - Defining changes in nasal immunity that favour propensity for pneumococcal colonisation in HIV-infected adults

The bacterium, Streptococcus pneumoniae (pneumococcus), is the major cause of pneumonia-related deaths worldwide. The pneumococcus resides in the nose and at the back of the throat, where it does not normally cause disease, but when conditions change it causes life-threatening illness, such as pneumonia. The pneumococcus is transmitted from person to person via the respiratory route. In Europe and North America, immunisation of children with the pneumococcal conjugate vaccine (PCV13) has greatly reduced the burden of pneumococcal disease and prevalence of the pneumococcus in the community because children no longer infect adults. Similar impact has not been observed in low income countries, such as Malawi, because children continue to carry pneumococci even after vaccination. Instead, the prevalence of the pneumococcus among HIV-infected adults on antiretroviral therapy (ART) has remained high despite the introduction of PCV13 as routine childhood vaccine in Malawi in 2011. Persistence of pneumococcus among HIV-infected adults on ART threatens to reverse the potential public health benefits of PCV13 that have been reported from high income countries. HIV-infected adults on ART serve as a haven for pneumococcus and may promote transmission of the bacterium in the community. However, the factors that promote persistence of pneumococcus among HIV-infected adults on ART are still unknown. I propose to recruit 100 Malawian adults, of which half will be HIV-uninfected and the other half will be ART-naïve HIV-infected. I will collect samples from the nose from all study participants and follow them up for 12months. I will quantify the number of times an individual is found with the pneumococcus in their nose, and compare this between the study groups. I will also investigate differences in immune parameters in the nose between the study groups. This comparison will also focus on relating the changes in the immune parameters in the nose with the number of times an individual is found with the pneumococcus in their nose. This will generate information on some of the factors that make HIV-infected infected adults on ART more susceptible to the pneumococcus. Furthermore, I will grow cells obtained from the nose of HIV-infected and uninfected adults in laboratory to generate a deeper understanding of how they interact with pneumococcus. I anticipate that this research study will will improve current understanding of why the pneumococcus is persistently found among HIV-infected adults on ART. This work will allow choices in optimal therapy against HIV and optimal vaccination strategies against pneumococcus, that could significantly impact pneumococcal transmission and disease in high transmission settings.

Streptococcus pneumoniae is a leading cause of morbidity and mortality in infants, immunocompromised individuals and the elderly. Pneumococcal carriage precedes disease and is important for transmission. Surveillance data from Malawi demonstrates persistently high pneumococcal carriage among antiretroviral therapy (ART)-experienced HIV-infected adults despite the introduction of pneumococcal conjugate vaccine (PCV)13 vaccine as routine childhood vaccine in Malawi in 2011, implying that the herd immunity benefits of vaccination are not robust in this setting. Due to the implementation of HIV "test and treat" strategy, the number of HIV-infected adults on ART will expand tremendously over the next 10 years. An increase in the pneumococcal transmission reservoir will threaten the public health benefits of pneumococcal vaccination. The factors behind this persistently high pneumococcal carriage remain unknown. I hypothesise that dysregulated local nasal innate immunity promotes increased propensity to pneumococcal carriage in HIV-infected adults. I propose to recruit 50 HIV-uninfected and 50 ART-naïve HIV-infected adults, and follow them up for 12 months. Nasopharyngeal swabs and nasosorption samples will be collected monthly, while blood and nasal cells will also be collected at recruitment and 12 months. As per national "test and treat" guidelines, all ART-naïve HIV-infected individuals will be initiated on ART. Pneumococcal carriage incidence will be compared between the study groups. Experiments will investigate the relationship between cytokine profiles, nasal cell phenotypes and nasal transcriptome signatures to pneumococcal carriage incidences. This work will generate information that will allow choices in optimal HIV therapy and optimal vaccination strategies to impact pneumococcal transmission and disease in high transmission settings.

The proposed research will benefit HIV-infected adults, researchers, policymakers, and the community at large. For HIV-infected adults, an understanding of the HIV-mediated perturbations in the nasal mucosa and the degree to which they are impacted by antiretroviral therapy, will allow choices in optimal HIV therapy and optimal vaccination strategies that could help restore nasal immunity and subsequently reduce the burden of respiratory infections in this population. Anti-retroviral therapy (ART) has been a tremendous success but it is now widely accepted that other interventions to augment ART are needed to sustain and improve the gains made by this life-saving intervention. For the researchers, the findings of this study will enhance our knowledge of HIV-mediated perturbations in the nasal mucosa that lead to persistently high prevalence of pneumococcal carriage in HIV-infected adults on antiretroviral therapy. Furthermore, this research study has a PhD studentship built into it, which provides an excellent opportunity to contribute to the training of the next generation of research scientists in Africa. For policymakers, findings from this study will provide further evidence to support introduction of interventions targeting HIV-infected adults on ART, to reduce pneumococcal transmission and subsequent pneumococcal disease. Vaccines targeting the rapidly-expanding population of HIV-infected adults on ART, who are a potential source of pneumococcal transmission are urgently needed. For the community, knowledge gained from this research study will contribute to development of novel interventions to control pneumococcal transmission and disease in the community. A reduction in pneumococcal transmission and disease is an important goal for improving the health of people living in high disease burden settings, like Malawi. This will translate into healthy and economically-productive communities. Every life counts.