Luicer A. Ingasia

University of the Witwatersrand

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Edwin Kamau

Walter Reed National Military Medical Center

Hoseah M. Akala

United States Army Medical Research Directorate - Africa

Ben Andagalu

United States Army Medical Research Directorate - Africa

Lorna J. Chebon

United States Army Medical Research Directorate - Africa

Benjamin Opot

Kenya Medical Research Institute

Dennis W. Juma

Kenya Medical Research Institute

Redemptah Yeda

United States Army Medical Research Directorate - Africa

Jinal N. Bhiman

University of the Witwatersrand

Dorcas Maruapula

Botswana Harvard AIDS Institute Partnership

Daniel G. Amoako

University of KwaZulu-Natal

Cooperative Institutions

University of KwaZulu-Natal

140

Kenya Medical Research Institute

129

Stellenbosch University

110

Africa Centres for Disease Control and Prevention

National Health Laboratory Service

Redeemer's University

Institut Pasteur

United States Army Medical Research Directorate - Africa

University of the Witwatersrand

University of Ghana

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Global and regional dispersal patterns of hepatitis B virus genotype E from and in Africa: A full-genome molecular analysis

PLoS ONE (2020)

Luicer A. Ingasia Evangelia Georgia Kostaki Dimitrios Paraskevis Anna Kramvis

Description of the spatial characteristics of viral dispersal is important in understanding the history of infections. Nine hepatitis B virus (HBV) genotypes (A-I), and a putative 10th genotype (J), with distinct geographical distribution, are recognized. In sub-Saharan Africa (sub)-genotypes A1, D3 and E circulate, with E predominating in western Africa (WA), where HBV is hyperendemic. The low genetic diversity of genotype E (HBV/E) suggests its recent emergence. Our aim was to study the dispersal of HBV/E using full-length, non-redundant and non-recombinant sequences available in public databases. HBV/E was confirmed, and the phylogeny reconstruction performed using maximum likelihood (ML) with bootstrapping. Phylogeographic analysis was conducted by reconstruction of ancestral states using the criterion of parsimony on the estimated ML phylogeny. 46.5% of HBV/E sequences were found within monophyletic clusters. Country-wise analysis revealed the existence of 50 regional clusters. Sequences from WA were located close to the root of the tree, indicating this region as the most probable origin of the HBV/E epidemic and expanded to other geographical regions, within and outside of Africa. A localized dispersal was observed with sequences from Nigeria and Guinea as compared to other WA countries. Based on the sequences available in the databases, the phylogenetic results suggest that European strains originated primarily from WA whereas a majority of American strains originated in Western Central Africa. The differences in regional dispersal patterns of HBV/E suggest limited cross-border transmissions because of restricted population movements.

Viral phylodynamics

Monophyly

10.1371/journal.pone.0240375

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Citations (25)

Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa

Nature (2022)

Raquel Viana Sikhulile Moyo Daniel G. Amoako Houriiyah Tegally Cathrine Scheepers

Abstract The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively 1–3 . In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function 4 . Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.

10.1038/s41586-022-04411-y

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Citations (1,581)

Plasmodium interspecies interactions during a period of increasing prevalence of Plasmodium ovale in symptomatic individuals seeking treatment: an observational study

The Lancet Microbe (2021)

Hoseah M. Akala Oliver J. Watson Kenneth K. Mitei Dennis W. Juma Robert Verity

The epidemiology and severity of non-falciparum malaria in endemic settings has garnered little attention. We aimed to characterise the prevalence, interaction, clinical risk factors, and temporal trends of non-falciparum Plasmodium species among symptomatic individuals presenting at health-care facilities in endemic settings of Kenya.We diagnosed and analysed infecting malaria species (Plasmodium falciparum, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium malariae) via PCR in clinical samples collected between March 1, 2008, and Dec 31, 2016, from six hospitals located in different regions of Kenya. We recruited patients aged 6 months or older who presented at outpatient departments with symptoms of malaria or tested positive for uncomplicated malaria by malaria rapid diagnostic test. Descriptive statistics were used to describe the prevalence and distribution of Plasmodium species. A statistical model was designed and used for estimating the frequency of Plasmodium species and assessing interspecies interactions. Mixed-effect linear regression models with random slopes for each location were used to test for change in prevalence over time.Samples from 2027 symptomatic participants presenting at care facilities were successfully analysed for all Plasmodium species. 1469 (72·5%) of the samples were P falciparum single-species infections, 523 (25·8%) were mixed infections, and only 35 (1·7%) were single non-falciparum species infections. 452 (22·3%) were mixed infections containing P ovale spp. A likelihood-based model calculation of the population frequency of each species estimated a significant within-host interference between P falciparum and P ovale curtisi. Mixed-effect logistic regression models identified a significant increase in P ovale wallikeri (2·1% per year; p=0·043) and P ovale curtisi (0·7% per year; p=0·0002) species over time, with a reciprocal decrease in P falciparum single-species infections (2·5% per year; p=0·0065). The frequency of P malariae infections did not significantly change over time. Risk of P falciparum infections presenting with fever was lower if co-infected with P malariae (adjusted odds ratio 0·43, 95% CI 0·25-0·74; p=0·0023).Our results show a prevalence of non-falciparum species infections of 27·5% among symptomatic individuals presenting at care facilities, which is higher than expected from previous cross-sectional surveys. The proportion of infections with P ovale wallikeri and P ovale curtisi was observed to significantly increase over the period of study, which could be due to attenuated responsiveness of these species to malaria drug treatment. The increase in frequency of P ovale spp could threaten the malaria control efforts in Kenya and pose increased risk of malaria to travellers.Armed Forces Health Surveillance Branch and its Global Emerging Infections Surveillance Section.

Plasmodium ovale

Plasmodium malariae

Plasmodium (life cycle)

Rapid diagnostic test

10.1016/s2666-5247(21)00009-4

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Citations (43)

Genetically Determined Response to Artemisinin Treatment in Western Kenyan Plasmodium falciparum Parasites

PLoS ONE (2016)

Lorna J. Chebon Bidii S. Ngalah Luicer A. Ingasia Dennis W. Juma Peninah Muiruri

Genetically determined artemisinin resistance in Plasmodium falciparum has been described in Southeast Asia. The relevance of recently described Kelch 13-propeller mutations for artemisinin resistance in Sub-Saharan Africa parasites is still unknown. Southeast Asia parasites have low genetic diversity compared to Sub-Saharan Africa, where parasites are highly genetically diverse. This study attempted to elucidate whether genetics provides a basis for discovering molecular markers in response to artemisinin drug treatment in P. falciparum in Kenya. The genetic diversity of parasites collected pre- and post- introduction of artemisinin combination therapy (ACT) in western Kenya was determined. A panel of 12 microsatellites and 91 single nucleotide polymorphisms (SNPs) distributed across the P. falciparum genome were genotyped. Parasite clearance rates were obtained for the post-ACT parasites. The 12 microsatellites were highly polymorphic with post-ACT parasites being significantly more diverse compared to pre-ACT (p < 0.0001). The median clearance half-life was 2.55 hours for the post-ACT parasites. Based on SNP analysis, 15 of 90 post-ACT parasites were single-clone infections. Analysis revealed 3 SNPs that might have some causal association with parasite clearance rates. Further, genetic analysis using Bayesian tree revealed parasites with similar clearance phenotypes were more closely genetically related. With further studies, SNPs described here and genetically determined response to artemisinin treatment might be useful in tracking artemisinin resistance in Kenya.

10.1371/journal.pone.0162524

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Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa

Nature (2022)

Raquel Viana Sikhulile Moyo Daniel G. Amoako Houriiyah Tegally Cathrine Scheepers

The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively1–3. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function4. Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity. The genomic profile and early transmission dynamics of the Omicron strain of SARS-CoV-2.

Strain (injury)

Herd Immunity

10.1038/d41586-021-03832-5

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Citations (71)

Polymorphisms in Pf mdr1 , Pf crt , and Pf nhe1 Genes Are Associated with Reduced In Vitro Activities of Quinine in Plasmodium falciparum Isolates from Western Kenya

Antimicrobial Agents and Chemotherapy (2014)

Jelagat Cheruiyot Luicer A. Ingasia Angela A. Omondi Dennis W. Juma Benjamin Opot

ABSTRACT In combination with antibiotics, quinine is recommended as the second-line treatment for uncomplicated malaria, an alternative first-line treatment for severe malaria, and for treatment of malaria in the first trimester of pregnancy. Quinine has been shown to have frequent clinical failures, and yet the mechanisms of action and resistance have not been fully elucidated. However, resistance is linked to polymorphisms in multiple genes, including multidrug resistance 1 (Pf mdr1 ), the chloroquine resistance transporter (Pf crt ), and the sodium/hydrogen exchanger gene (Pf nhe1 ). Here, we investigated the association between in vitro quinine susceptibility and genetic polymorphisms in Pf mdr1 codons 86 and 184, Pf crt codon 76, and Pf nhe1 ms4760 in 88 field isolates from western Kenya. In vitro activity was assessed based on the drug concentration that inhibited 50% of parasite growth (the IC 50 ), and parasite genetic polymorphisms were determined from DNA sequencing. Data revealed there were significant associations between polymorphism in Pf mdr1 -86Y, Pf mdr1 -184F, or Pf crt -76T and quinine susceptibility ( P < 0.0001 for all three associations). Eighty-two percent of parasites resistant to quinine carried mutant alleles at these codons (Pf mdr1 -86Y, Pf mdr1 -184F, and Pf crt -76T), whereas 74% of parasites susceptible to quinine carried the wild-type allele (Pf mdr1 -N86, Pf mdr1 -Y184, and Pf crt -K76, respectively). In addition, quinine IC 50 values for parasites with Pf nhe1 ms4760 3 DNNND repeats were significantly higher than for those with 1 or 2 repeats ( P = 0.033 and P = 0.0043, respectively). Clinical efficacy studies are now required to confirm the validity of these markers and the importance of parasite genetic background.

Quinine

10.1128/aac.02472-14

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Citations (27)

Molecular characterization of hepatitis B virus (HBV) isolated from a pediatric case of acute lymphoid leukemia, with a delayed response to antiviral treatment: a case report

BMC Pediatrics (2022)

Chien‐Yu Chen Christina Hajinicolaou Priya Walabh Luicer A. Ingasia Ernest Song

Abstract Background Tenofovir disoproxil fumarate (TDF) is effectively used as the first-line antiviral for chronic hepatitis B virus (HBV) infection in adults and children older than 12 years. To date, no confirmed case of virologic breakthrough (VBT) in a pediatric case has been reported. Case presentation Here we describe a case of a 5-year old, asymptomatically infected with HBV infection two months after chemotherapy for precursor B acute lymphoblastic leukemia (ALL). Although the 5-year old male is South African, his family originated from Guinea. At the end of the one-year follow-up, the infection progressed to chronic HBV infection, with a high viral load. At 36 weeks (8 months) post-treatment with lamivudine (LAM), there was a partial virologic response (PVR) and after 61 weeks (14 months), he was switched to TDF rescue monotherapy. Even with TDF treatment, he still experienced VBT and subsequent PVR. The full-length genome of HBV isolated 78 weeks after the switch to rescue TDF monotherapy was sequenced and belonged to genotype E. In addition to the LAM mutations (rtS256G and rtM267L), missense mutations in B-cell, T-cell, HLA class I and II-restricted epitopes emerged, which were to evade and escape host surveillance, leading to delayed viral clearance, persistence and disease progression. Two further events of VBT occurred between weeks 113 and 141 of TDF rescue-therapy. Viral loads and liver enzymes are normalizing progressively with long-term therapy. Conclusion Although the host immune reconstitution may be delayed, prolonged TDF treatment was effective in treating this pediatric case of HBV infection with VBT and PVR.

Hepatitis B

10.1186/s12887-022-03204-6

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Citations (2)

Molecular Characterization of the Cytochrome b Gene and In Vitro Atovaquone Susceptibility of Plasmodium falciparum Isolates from Kenya

Antimicrobial Agents and Chemotherapy (2015)

Luicer A. Ingasia Hoseah M. Akala M. O. Imbuga Benjamin Opot Fredrick Eyase

The prevalence of a genetic polymorphism(s) at codon 268 in the cytochrome b gene, which is associated with failure of atovaquone-proguanil treatment, was analyzed in 227 Plasmodium falciparum parasites from western Kenya. The prevalence of the wild-type allele was 63%, and that of the Y268S (denoting a Y-to-S change at position 268) mutant allele was 2%. There were no pure Y268C or Y268N mutant alleles, only mixtures of a mutant allele(s) with the wild type. There was a correlation between parasite 50% inhibitory concentration (IC50) and parasite genetic polymorphism; mutant alleles had higher IC50s than the wild type.

Atovaquone

Wild type

10.1128/aac.03956-14

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Citations (7)

Temporal trends in prevalence of Plasmodium falciparum molecular markers selected for by artemether–lumefantrine treatment in pre-ACT and post-ACT parasites in western Kenya

International Journal for Parasitology Drugs and Drug Resistance (2015)

Angela O. Achieng Peninah Muiruri Luicer A. Ingasia Benjamin Opot Dennis W. Juma

Artemether-lumefantrine (AL) became the first-line treatment for uncomplicated malaria in Kenya in 2006. Studies have shown AL selects for SNPs in pfcrt and pfmdr1 genes in recurring parasites compared to the baseline infections. The genotypes associated with AL selection are K76 in pfcrt and N86, 184F and D1246 in pfmdr1. To assess the temporal change of these genotypes in western Kenya, 47 parasite isolates collected before (pre-ACT; 1995-2003) and 745 after (post-ACT; 2008-2014) introduction of AL were analyzed. In addition, the associations of parasite haplotype against the IC50 of artemether and lumefantrine, and clearance rates were determined. Parasite genomic DNA collected between 1995 and 2014 was analyzed by sequencing or PCR-based single-base extension on Sequenom MassARRAY. IC50s were determined for a subset of the samples. One hundred eighteen samples from 2013 to 2014 were from an efficacy trial of which 68 had clearance half-lives. Data revealed there were significant differences between pre-ACT and post-ACT genotypes at the four codons (chi-square analysis; p < 0.0001). The prevalence of pfcrt K76 and N86 increased from 6.4% in 1995-1996 to 93.2% in 2014 and 0.0% in 2002-2003 to 92.4% in 2014 respectively. Analysis of parasites carrying pure alleles of K + NFD or T + YYY haplotypes revealed that 100.0% of the pre-ACT parasites carried T + YYY and 99.3% of post-ACT parasites carried K + NFD. There was significant correlation (p = 0.04) between lumefantrine IC50 and polymorphism at pfmdr1 codon 184. There was no difference in parasite clearance half-lives based on genetic haplotype profiles. This study shows there is a significant change in parasite genotype, with key molecular determinants of AL selection almost reaching saturation. The implications of these findings are not clear since AL remains highly efficacious. However, there is need to closely monitor parasite genotypic, phenotypic and clinical dynamics in response to continued use of AL in western Kenya.

Artemether/lumefantrine

Lumefantrine

10.1016/j.ijpddr.2015.05.005

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Citations (47)

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

Science (2022)

Houriiyah Tegally James Emmanuel San Matthew Cotten Monika Moir Bryan Tegomoh

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century.

Pandemic

Preparedness

10.1126/science.abq5358

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Citations (107)