The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis

The global tuberculosis (TB) epidemic and the spread of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host-directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals

The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-10-17T12:06:00Z No. of bitstreams: 1 Ahidjo BA The antifibrotic....pdf: 2168068 bytes, checksum: b8a4ff8bbb712343a8af6858f83f9cf9 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-10-17T12:32:58Z (GMT) No. of bitstreams: 1 Ahidjo BA The antifibrotic....pdf: 2168068 bytes, checksum: b8a4ff8bbb712343a8af6858f83f9cf9 (MD5)Made available in DSpace on 2016-10-17T12:32:58Z (GMT). No. of bitstreams: 1 Ahidjo BA The antifibrotic....pdf: 2168068 bytes, checksum: b8a4ff8bbb712343a8af6858f83f9cf9 (MD5) Previous issue date: 2016-09-08NIHJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Howard Hughes Medical Institute. Chevy Chase, Maryland, USAJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Howard Hughes Medical Institute. Chevy Chase, Maryland, USAJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Johns Hopkins University School of Medicine. Molecular and Comparative Pathobiology. Baltimore,MD, USAJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Université des Sciences, des Techniques et des Technologies de Bamako. Bamako, MaliJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Johns Hopkins University School of Medicine. Center for Infection and Inflammation Imaging Research. Baltimore, MD, USA / Johns Hopkins University School of Medicine. Department of Pediatrics. Baltimore, MD, USAJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USAJohns Hopkins University School of Medicine. Molecular and Comparative Pathobiology. Baltimore, MD, USAFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. 7Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação. Salvador, BA, Brasil / Fundação José Silveira. Instituto Brasileiro para a Investigação da Tuberculose. Salvador, BA, BrasilJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Johns Hopkins University School of Medicine. Center for Infection and Inflammation Imaging Research. Baltimore, MD, USA / Johns Hopkins University School of Medicine. Department of Pediatrics. Baltimore, MD, USAJohns Hopkins University School of Medicine. Center for Tuberculosis Research. Baltimore, MD, USA / Howard Hughes Medical Institute. Chevy Chase, Maryland, USAPirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings