The disparate burden of infectious diseases

The age of modern medicine brought about groundbreaking methods to combat pathogens and improve our quality of life. From simply understanding medical asepsis, to the discovery of antibiotics and vaccines, these advances have been used to prevent, treat, and cure numerous infectious and parasitic diseases. For most human pathogens the endgame is global eradication, as has been achieved for smallpox and earmarked for poliomyelitis and Dracunculiasis. But regional elimination and control strategies are more realistic, especially when prophylactic or therapeutic interventions are available, and have led to a steady decline in communicable diseases over the past ten years. As a result, the major global disease burden has shifted to noncommunicable diseases (NCD).

Except there are still millions of people who die each year because of infectious and parasitic diseases. And where you live matters [1].

Disease burdens are calculated by measuring Disability-adjusted life years (DALYs) which considers years lost due to early mortality as well as years lost to morbidity. In 2019, the total disease burden (DALYs) [2, 3] attributed to communicable, maternal, neonatal, and nutritional diseases in low-income and lower-middle-income countries was 54.99% and 35.78% respectively, whereas in high-income countries it was much lower, only 4.52%. Sub-Saharan Africa was found to have the highest fraction of pathogen-associated DALYs (61.5%), followed by South Asia (28.5%) [1]. Of the 85 pathogens identified in the report, tuberculosis (TB), malaria, and HIV/AIDS contributed to the highest global DALY counts [1]. The COVID-19 pandemic did cause a shift in disease burdens (Table 1), with low-income, lower-middle-income, and high-income countries attributing 55.75%, 38.56% and 10.48% to communicable, maternal, neonatal, and nutritional diseases in 2021. However, the true impact of the COVID pandemic on infectious disease burdens is likely to take years to map. Disruptions to essential vaccine and drug manufacturing and supply chains, coupled with reduced routine testing and surveillance will have left many vulnerable.

Important lessons have emerged from the COVID pandemic. Infectious diseases spread regardless of borders, equitable access to vaccines should be a global priority, better public health initiatives are needed to address vaccine hesitancy, and disinformation is just as dangerous as a pandemic. But it also showed us that when faced with a global health emergency, people from various disciplines rallied together to produce vaccines and treatments in record time. Imagine if we were able to apply the same philosophies to other infectious diseases that, for decades, have been without adequate vaccines or cures.

This may well be on the horizon. Next-generation vaccine technologies, many of which complement current gene and cell therapy approaches, were expanded and fast-tracked during the pandemic, as discussed in this issue by Bloom et al. This includes mRNA technology, viral-vector based vaccines and therapies, as well as virus-like particle platforms, that could be used to develop active or passive immunoprophylaxis. In this special issue, we dive into the field of gene therapy and next-generation vaccines for chronic and acute infectious diseases including Hepatitis B virus (HBV), Human immunodeficiency virus (HIV), malaria, Respiratory syncytial virus (RSV), and Marburg virus disease (MVD) (Fig. 1).

The global prevalence, annual infection and mortality rates, availability of vaccines and curative therapeutics, and average Disability-adjusted life years (DALYs; depicted as total counts) are shown for the five infectious diseases covered in this special issue: Hepatitis B virus (HBV), Human immunodeficiency virus (HIV), malaria, Respiratory syncytial virus (RSV), and Marburg virus disease (MVD). Statistics are derived from the most recent infectious disease-specific World Health Organisation (WHO) fact sheets and/or reports, based on data collected in 2022. Average DALYs for 2019 as reported by IHME Pathogen Core Group [1]. CFR - case fatality ratio. Image created using BioRender.com.

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For chronic diseases like HBV and HIV, gene or cell therapy may provide a functional cure for the millions of people who are currently infected (up to 300 million chronic HBV at risk for cancer, and 39 million HIV). Alarmingly, the number of HBV-associated deaths per year continues to increase, exceeding 1 million in 2022. Jacobs et al. review the potential of viral vector mediated gene editing tools to provide a functional cure for chronic HBV infection. In the case of HIV, large-scale rollout of antiretroviral treatment has had a major impact reducing AIDS related deaths, however the annual decline in the number of newly infected individuals has plateaued, suggesting alternative interventions are needed. To target HIV reservoirs, Hetrick et al. describe a Rev-dependent lentiviral particle that aims to prevent viral rebound following ART termination in rhesus macaques, while Burdo et al. report on the preclinical safety and biodistribution of their HIV proviral DNA targeting gene therapy EBT-001, which uses AAV9 to deliver dual guide RNAs and an SaCas9.

CRISPR technologies have further applications in the control of vector-borne diseases such as malaria. Genetic modification and gene drives aimed at managing mosquito populations or preventing malaria parasite development are reviewed here by Oliver and Naidoo. This approach could complement current physical and chemical vector control strategies, and newly implemented routine vaccination schedules in Africa.

AAV-based expression of monoclonal antibodies provides an avenue for prophylactic or therapeutic treatment of infectious diseases. Using an AAV6.2FF vector to express RSV antibodies, Rghei et al. show that sterilising immunity can be achieved in preclinical RSV challenge studies, and that this vectored immunoprophylaxis results in passive transfer of antibodies to progeny. Achieving passive immunity is an important milestone for RSV vaccines, as infants bear the highest burden of disease. The same team showed a similar approach for the prevention of lethal Marburg virus infection in mice and achieved sustained expression of MR191 human IgG antibodies in sheep. MVD is a zoonotic disease that often results in fatal haemorrhagic fever, emphasising the importance of implementing one health approaches to prevent the spread of infectious diseases.

Finally, a cautionary perspective from Aubert et al., which reviews AAV vector neurotoxicity reported in preclinical and clinical gene therapy studies, highlighting the importance of comprehensive viral vector characterisation for gene therapy and vaccine approaches.

In conclusion, focusing research efforts on advancing gene therapy and next-generation vaccine technologies to tackle current and emerging pathogens will not only reduce the burden of infectious diseases, but also facilitate future pandemic preparedness through the creation of new prophylactic and therapeutic platforms.