register interest

Dr George M Warimwe MRCVS

Research Area: Immunology
Technology Exchange: Vaccine production and evaluation
Scientific Themes: Tropical Medicine & Global Health
Keywords: Rift Valley Fever, Vaccine, One Health and Middle East Respiratory Syndrome (MERS)
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I trained as a veterinary surgeon at the University of Nairobi, Kenya and completed a PhD in the epidemiology of childhood malaria in 2010. I later joined the Jenner Institute where, with support from Wellcome and other funders, I initiated a One Health vaccine programme in which vaccines against Rift Valley Fever and other zoonotic disease indications are co-developed for deployment in humans and the respective animal hosts of infection. Using this approach I have developed a novel chimpanzee adenovirus vectored Rift Valley Fever vaccine that is highly efficacious in multiple target livestock species. The vaccine is just about to enter human phase I clinical trials in the UK and East Africa, and will be evaluated in parallel livestock field trials in Kenya. I also co-lead a similar One Health vaccine project for Middle East Respiratory Syndrome (MERS) aimed at developing a MERS vaccine for deployment in camels and humans.

More recently I have begun an arbovirus epidemiology programme at the Wellcome Programme in Kenya. My focus is on estimating long term transmission trends and case burden of flaviviruses (e.g. Dengue), alphaviruses (e.g. Chikungunya, Onyong'nyong') and bunyaviruses (e.g. Rift Valley Fever) in coastal Kenya, where recurrent outbreaks of these diseases are known to occur. These studies will inform target product profiles for candidate vaccines against these arboviral threats and underpin the design of clinical trials for vaccine efficacy estimation.

Name Department Institution Country
Dr Bryan Charleston Jenner Institute Oxford University, The Pirbright Institute United Kingdom
Dr Alejandro Brun Centro de Investigación en Sanidad Animal Instituto Nacional de Investigación Agraria y Alimentaria, Madrid Spain
Dr Vishvanath Nene International Livestock Research Institute Kenya
Professor Adrian VS Hill Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Professor James A Berkley Tropical Medicine Oxford University, Kilifi Kenya
Professor Philip Bejon Tropical Medicine Oxford University, Kilifi Kenya
Dr Rosemary Sang Kenya Medical Research Institute Kenya
Professor Thomas A. Bowden Structural Biology Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Sarah C Gilbert Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Dr Baptiste Dungu MCI Sante-Animale Morocco
Professor Sumi Biswas Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Professor James Nokes KEMRI-Wellcome Trust Research Programme Kenya
Warimwe GM, Purushotham J, Perry BD, Hill AVS, Gilbert SC, Dungu B, Charleston B. 2018. Tackling human and animal health threats through innovative vaccinology in Africa AAS Open Research, 1 pp. 18-18. | Read more

Munster VJ, Wells D, Lambe T, Wright D, Fischer RJ, Bushmaker T, Saturday G, van Doremalen N, Gilbert SC, de Wit E, Warimwe GM. 2017. Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model. NPJ Vaccines, 2 (1), pp. 28. | Show Abstract | Read more

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic virus that causes severe respiratory disease in humans with a case fatality rate close to 40%, but for which no vaccines are available. Here, we evaluated the utility of ChAdOx1, a promising replication-deficient simian adenovirus vaccine vector platform with an established safety profile in humans and dromedary camels, for MERS-CoV vaccine development. Using a transgenic lethal BALB/c MERS-CoV mouse model we showed that single dose intranasal or intramuscular immunisation with ChAdOx1 MERS, encoding full-length MERS-CoV Spike glycoprotein, is highly immunogenic and confers protection against lethal viral challenge. Immunogenicity and efficacy were comparable between immunisation routes. Together these data provide support for further evaluation of ChAdOx1 MERS vaccine in humans and dromedary camels, the animal reservoir of infection.

Gilbert SC, Warimwe GM. 2017. Rapid development of vaccines against emerging pathogens: The replication-deficient simian adenovirus platform technology. Vaccine, 35 (35 Pt A), pp. 4461-4464. | Show Abstract | Read more

Despite the fact that there had been multiple small outbreaks of Ebola Virus Disease, when a large outbreak occurred in 2014 there were no vaccines or drugs available for use. Clinical development of multiple candidate vaccines was then initiated in parallel with attempts to contain the outbreak but only one vaccine was eventually tested in a phase III trial. In order to be better prepared for future outbreaks of known human pathogens, platform technologies to accelerate vaccine development should be employed, allowing vaccine developers to take advantage of detailed knowledge of the vaccine platform and facilitating rapid progress to clinical trials and eventually to vaccine stockpiles. This review gives an example of one such vaccine platform, replication-deficient simian adenoviruses, and describes progress in human and livestock vaccine development for three outbreak pathogens, Ebola virus, Rift Valley Fever Virus and Middle East Respiratory Syndrome Coronavirus.

Alharbi NK, Padron-Regalado E, Thompson CP, Kupke A, Wells D, Sloan MA, Grehan K, Temperton N, Lambe T, Warimwe G et al. 2017. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine, 35 (30), pp. 3780-3788. | Show Abstract | Read more

The Middle East respiratory syndrome coronavirus (MERS-CoV) has infected more than 1900 humans, since 2012. The syndrome ranges from asymptomatic and mild cases to severe pneumonia and death. The virus is believed to be circulating in dromedary camels without notable symptoms since the 1980s. Therefore, dromedary camels are considered the only animal source of infection. Neither antiviral drugs nor vaccines are approved for veterinary or medical use despite active research on this area. Here, we developed four vaccine candidates against MERS-CoV based on ChAdOx1 and MVA viral vectors, two candidates per vector. All vaccines contained the full-length spike gene of MERS-CoV; ChAdOx1 MERS vaccines were produced with or without the leader sequence of the human tissue plasminogen activator gene (tPA) where MVA MERS vaccines were produced with tPA, but either the mH5 or F11 promoter driving expression of the spike gene. All vaccine candidates were evaluated in a mouse model in prime only or prime-boost regimens. ChAdOx1 MERS with tPA induced higher neutralising antibodies than ChAdOx1 MERS without tPA. A single dose of ChAdOx1 MERS with tPA elicited cellular immune responses as well as neutralising antibodies that were boosted to a significantly higher level by MVA MERS. The humoral immunogenicity of a single dose of ChAdOx1 MERS with tPA was equivalent to two doses of MVA MERS (also with tPA). MVA MERS with mH5 or F11 promoter induced similar antibody levels; however, F11 promoter enhanced the cellular immunogenicity of MVA MERS to significantly higher magnitudes. In conclusion, our study showed that MERS-CoV vaccine candidates could be optimized by utilising different viral vectors, various genetic designs of the vectors, or different regimens to increase immunogenicity. ChAdOx1 and MVA vectored vaccines have been safely evaluated in camels and humans and these MERS vaccine candidates should now be tested in camels and in clinical trials.

Dulal P, Wright D, Ashfield R, Hill AVS, Charleston B, Warimwe GM. 2016. Potency of a thermostabilised chimpanzee adenovirus Rift Valley Fever vaccine in cattle. Vaccine, 34 (20), pp. 2296-2298. | Show Abstract | Read more

Development of safe and efficacious vaccines whose potency is unaffected by long-term storage at ambient temperature would obviate major vaccine deployment hurdles and limit wastage associated with breaks in the vaccine cold chain. Here, we evaluated the immunogenicity of a novel chimpanzee adenovirus vectored Rift Valley Fever vaccine (ChAdOx1-GnGc) in cattle, following its thermostabilisation by slow desiccation on glass fiber membranes in the non-reducing sugars trehalose and sucrose. Thermostabilised ChAdOx1-GnGc vaccine stored for 6 months at 25, 37 or 45 ° C elicited comparable Rift Valley Fever virus neutralising antibody titres to those elicited by the 'cold chain' vaccine (stored at -80 ° C throughout) at the same dose, and these were within the range associated with protection against Rift Valley Fever in cattle. The results support the use of sugar-membrane thermostabilised vaccines in target livestock species.

Warimwe GM, Abdi AI, Muthui M, Fegan G, Musyoki JN, Marsh K, Bull PC. 2016. Serological Conservation of Parasite-Infected Erythrocytes Predicts Plasmodium falciparum Erythrocyte Membrane Protein 1 Gene Expression but Not Severity of Childhood Malaria. Infect Immun, 84 (5), pp. 1331-1335. | Show Abstract | Read more

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on P. falciparum-infected erythrocytes, is a major family of clonally variant targets of naturally acquired immunity to malaria. Previous studies have demonstrated that in areas where malaria is endemic, antibodies to infected erythrocytes from children with severe malaria tend to be more seroprevalent than antibodies to infected erythrocytes from children with nonsevere malaria. These data have led to a working hypothesis that PfEMP1 variants associated with parasite virulence are relatively conserved in structure. However, the longevity of such serologically conserved variants in the parasite population is unknown. Here, using infected erythrocytes from recently sampled clinical P. falciparum samples, we measured serological conservation using pools of antibodies in sera that had been sampled 10 to 12 years earlier. The serological conservation of infected erythrocytes strongly correlated with the expression of specific PfEMP1 subsets previously found to be associated with severe malaria. However, we found no association between serological conservation per se and disease severity within these data. This contrasts with the simple hypothesis that P. falciparum isolates with a serologically conserved group of PfEMP1 variants cause severe malaria. The data are instead consistent with periodic turnover of the immunodominant epitopes of PfEMP1 associated with severe malaria.

Warimwe GM, Gesharisha J, Carr BV, Otieno S, Otingah K, Wright D, Charleston B, Okoth E, Elena L-G, Lorenzo G et al. 2016. Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever. Sci Rep, 6 (1), pp. 20617. | Show Abstract | Read more

Rift Valley Fever virus (RVFV) causes recurrent outbreaks of acute life-threatening human and livestock illness in Africa and the Arabian Peninsula. No licensed vaccines are currently available for humans and those widely used in livestock have major safety concerns. A 'One Health' vaccine development approach, in which the same vaccine is co-developed for multiple susceptible species, is an attractive strategy for RVFV. Here, we utilized a replication-deficient chimpanzee adenovirus vaccine platform with an established human and livestock safety profile, ChAdOx1, to develop a vaccine for use against RVFV in both livestock and humans. We show that single-dose immunization with ChAdOx1-GnGc vaccine, encoding RVFV envelope glycoproteins, elicits high-titre RVFV-neutralizing antibody and provides solid protection against RVFV challenge in the most susceptible natural target species of the virus-sheep, goats and cattle. In addition we demonstrate induction of RVFV-neutralizing antibody by ChAdOx1-GnGc vaccination in dromedary camels, further illustrating the potency of replication-deficient chimpanzee adenovirus vaccine platforms. Thus, ChAdOx1-GnGc warrants evaluation in human clinical trials and could potentially address the unmet human and livestock vaccine needs.

Abdi AI, Warimwe GM, Muthui MK, Kivisi CA, Kiragu EW, Fegan GW, Bull PC. 2016. Global selection of Plasmodium falciparum virulence antigen expression by host antibodies. Sci Rep, 6 (1), pp. 19882. | Show Abstract | Read more

Parasite proteins called PfEMP1 that are inserted on the surface of infected erythrocytes, play a key role in the severe pathology associated with infection by the Plasmodium falciparum malaria parasite. These proteins mediate binding of infected cells to the endothelial lining of blood vessels as a strategy to avoid clearance by the spleen and are major targets of naturally acquired immunity. PfEMP1 is encoded by a large multi-gene family called var. Mutually-exclusive transcriptional switching between var genes allows parasites to escape host antibodies. This study examined in detail the patterns of expression of var in a well-characterized sample of parasites from Kenyan Children. Instead of observing clear inverse relationships between the expression of broad sub-classes of PfEMP1, we found that expression of different PfEMP1 groups vary relatively independently. Parasite adaptation to host antibodies also appears to involve a general reduction in detectable var gene expression. We suggest that parasites switch both between different PfEMP1 variants and between high and low expression states. Such a strategy could provide a means of avoiding immunological detection and promoting survival under high levels of host immunity.

Lorenzo G, López-Gil E, Warimwe GM, Brun A. 2015. Understanding Rift Valley fever: Contributions of animal models to disease characterization and control Molecular Immunology, 66 (1), pp. 78-88. | Show Abstract | Read more

© 2015 Elsevier Ltd. Rift Valley fever (RVF) is a mosquito-borne viral zoonosis with devastating health impacts in domestic ruminants and humans. Effective vaccines and accurate disease diagnostic tools are key components in the control of RVF. Animal models reproducing infection with RVF virus are of upmost importance in the development of these disease control tools. Rodent infection models are currently used in the initial steps of vaccine development and for the study of virus induced pathology. Translation of data obtained in these animal models to target species (ruminants and humans) is highly desirable but does not always occur. Small ruminants and non-human primates have been used for pathogenesis and transmission studies, and for testing the efficacy of vaccines and therapeutic antiviral compounds. However, the molecular mechanisms of the immune response elicited by RVF virus infection or vaccination are still poorly understood. The paucity of data in this area offers opportunities for new research activities and programs. This review summarizes our current understanding with respect to immunity and pathogenesis of RVF in animal models with a particular emphasis on small ruminants and non-human primates, including recent experimental infection data in sheep.

Warimwe GM, Fegan G, Kiragu EW, Musyoki JN, Macharia AW, Marsh K, Williams TN, Bull PC. 2014. An assessment of the impact of host polymorphisms on Plasmodium falciparum var gene expression patterns among Kenyan children. BMC Infect Dis, 14 (1), pp. 524. | Show Abstract | Read more

BACKGROUND: Host genotype accounts for a component of the variability in susceptibility to childhood Plasmodium falciparum malaria. However, despite numerous examples of host polymorphisms associated with tolerance or resistance to infection, direct evidence for an impact of host genetic polymorphisms on the in vivo parasite population is difficult to obtain. Parasite molecules whose expression is most likely to be associated with such adaptation are those that are directly involved in the host-parasite interaction. A prime candidate is the family of parasite var gene-encoded molecules on P. falciparum-infected erythrocytes, PfEMP1, which binds various host molecules and facilitates parasite sequestration in host tissues to avoid clearance by the spleen. METHODS: To assess the impact of host genotype on the infecting parasite population we used a published parasite var gene sequence dataset to compare var gene expression patterns between parasites from children with polymorphisms in molecules thought to interact with or modulate display of PfEMP1 on the infected erythrocyte surface: ABO blood group, haemoglobin S, alpha-thalassaemia, the T188G polymorphism of CD36 and the K29M polymorphism of ICAM1. RESULTS: Expression levels of 'group A-like' var genes, which encode a specific group of PfEMP1 variants previously associated with low host immunity and severe malaria, showed signs of elevation among children of blood group AB. No other host factor tested showed evidence for an association with var expression. CONCLUSIONS: Our preliminary findings suggest that host ABO blood group may have a measurable impact on the infecting parasite population. This needs to be verified in larger studies.

Busquets N, Lorenzo G, Lopez-Gil E, Rivas R, Solanes D, Galindo-Cardiel I, Xavier Abad F, Rodriguez F, Bensaid A, Warimwe G et al. 2014. Efficacy assessment of an MVA vectored Rift Valley Fever vaccine in lambs ANTIVIRAL RESEARCH, 108 pp. 165-172. | Read more

Lorenzo G, López-Gil E, Warimwe GM, Brun A. 2015. Understanding Rift Valley fever: contributions of animal models to disease characterization and control. Mol Immunol, 66 (1), pp. 78-88. | Show Abstract | Read more

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis with devastating health impacts in domestic ruminants and humans. Effective vaccines and accurate disease diagnostic tools are key components in the control of RVF. Animal models reproducing infection with RVF virus are of upmost importance in the development of these disease control tools. Rodent infection models are currently used in the initial steps of vaccine development and for the study of virus induced pathology. Translation of data obtained in these animal models to target species (ruminants and humans) is highly desirable but does not always occur. Small ruminants and non-human primates have been used for pathogenesis and transmission studies, and for testing the efficacy of vaccines and therapeutic antiviral compounds. However, the molecular mechanisms of the immune response elicited by RVF virus infection or vaccination are still poorly understood. The paucity of data in this area offers opportunities for new research activities and programs. This review summarizes our current understanding with respect to immunity and pathogenesis of RVF in animal models with a particular emphasis on small ruminants and non-human primates, including recent experimental infection data in sheep.

Busquets N, Lorenzo G, López-Gil E, Rivas R, Solanes D, Galindo-Cardiel I, Abad FX, Rodríguez F, Bensaid A, Warimwe G et al. 2014. Efficacy assessment of an MVA vectored Rift Valley Fever vaccine in lambs. Antiviral Res, 108 (1), pp. 165-172. | Show Abstract | Read more

The present study has evaluated the protection conferred by a single subcutaneous dose of a modified vaccinia virus Ankara (MVA) vectored vaccine encoding the Rift Valley Fever virus (RVFV) glycoproteins Gn and Gc in lambs. Three groups of six to seven lambs were immunized as follows: one group received the vaccine (termed rMVA-GnGc), a second group received an MVA vector (vector control) and a third group received saline solution (non-vaccinated control). Fourteen days later, all animals were subcutaneously challenged with 10(5) TCID50 of the virulent RVFV isolate 56/74 and vaccine efficacy assessed using standard endpoints. Two lambs (one from the vaccine group and one from the vector control group) succumbed to RVFV challenge, showing characteristic liver lesions. Lambs from both the vector control and non-vaccinated groups were febrile from days 2 to 5 post challenge (pc) while those in the rMVA-GnGc group showed a single peak of pyrexia at day 3 pc. RVFV RNA was detected in both nasal and oral swabs from days 3 to 7 pc in some lambs from the vector control and non-vaccinated groups, but no viral shedding could be detected in the surviving lambs vaccinated with rMVA-GnGc. Together, the data suggest that a single dose of the rMVA-GnGc vaccine may be sufficient to reduce RVFV shedding and duration of viremia but does not provide sterile immunity nor protection from disease. Further optimization of this vaccine approach in lambs is warranted.

Abdi AI, Fegan G, Muthui M, Kiragu E, Musyoki JN, Opiyo M, Marsh K, Warimwe GM, Bull PC. 2014. Plasmodium falciparum antigenic variation: relationships between widespread endothelial activation, parasite PfEMP1 expression and severe malaria. BMC Infect Dis, 14 (1), pp. 170. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) is a family of variant surface antigens (VSA) that mediate the adhesion of parasite infected erythrocytes to capillary endothelial cells within host tissues. Opinion is divided over the role of PfEMP1 in the widespread endothelial activation associated with severe malaria. In a previous study we found evidence for differential associations between defined VSA subsets and specific syndromes of severe malaria: group A-like PfEMP1 expression and the "rosetting" phenotype were associated with impaired consciousness and respiratory distress, respectively. This study explores the involvement of widespread endothelial activation in these associations. METHODS: We used plasma angiopoietin-2 as a marker of widespread endothelial activation. Using logistic regression analysis, we explored the relationships between plasma angiopoietin-2 levels, parasite VSA expression and the two syndromes of severe malaria, impaired consciousness and respiratory distress. RESULTS: Plasma angiopoietin-2 was associated with both syndromes. The rosetting phenotype did not show an independent association with respiratory distress when adjusted for angiopoietin-2, consistent with a single pathogenic mechanism involving widespread endothelial activation. In contrast, group A-like PfEMP1 expression and angiopoietin-2 maintained independent associations with impaired consciousness when adjusted for each other. CONCLUSION: The results are consistent with multiple pathogenic mechanisms leading to severe malaria and heterogeneity in the pathophysiology of impaired consciousness. The observed association between group A-like PfEMP1 and impaired consciousness does not appear to involve widespread endothelial activation.

Warimwe GM, Lorenzo G, Lopez-Gil E, Reyes-Sandoval A, Cottingham MG, Spencer AJ, Collins KA, Dicks MDJ, Milicic A, Lall A et al. 2013. Immunogenicity and efficacy of a chimpanzee adenovirus-vectored Rift Valley fever vaccine in mice. Virol J, 10 (1), pp. 349. | Show Abstract | Read more

BACKGROUND: Rift Valley Fever (RVF) is a viral zoonosis that historically affects livestock production and human health in sub-Saharan Africa, though epizootics have also occurred in the Arabian Peninsula. Whilst an effective live-attenuated vaccine is available for livestock, there is currently no licensed human RVF vaccine. Replication-deficient chimpanzee adenovirus (ChAd) vectors are an ideal platform for development of a human RVF vaccine, given the low prevalence of neutralizing antibodies against them in the human population, and their excellent safety and immunogenicity profile in human clinical trials of vaccines against a wide range of pathogens. METHODS: Here, in BALB/c mice, we evaluated the immunogenicity and efficacy of a replication-deficient chimpanzee adenovirus vector, ChAdOx1, encoding the RVF virus envelope glycoproteins, Gn and Gc, which are targets of virus neutralizing antibodies. The ChAdOx1-GnGc vaccine was assessed in comparison to a replication-deficient human adenovirus type 5 vector encoding Gn and Gc (HAdV5-GnGc), a strategy previously shown to confer protective immunity against RVF in mice. RESULTS: A single immunization with either of the vaccines conferred protection against RVF virus challenge eight weeks post-immunization. Both vaccines elicited RVF virus neutralizing antibody and a robust CD8+ T cell response. CONCLUSIONS: Together the results support further development of RVF vaccines based on replication-deficient adenovirus vectors, with ChAdOx1-GnGc being a potential candidate for use in future human clinical trials.

Naranbhai V, Hill AVS, Abdool Karim SS, Naidoo K, Abdool Karim Q, Warimwe GM, McShane H, Fletcher H. 2014. Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy. J Infect Dis, 209 (4), pp. 500-509. | Show Abstract | Read more

BACKGROUND: Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the "ML ratio") was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases. METHODS: The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted. RESULTS: The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38-61.54), 16.36 (95% CI, 12.39-21.23), and 51.80 (95% CI, 23.10-101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4(+) T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39-4.40; P = .002). CONCLUSIONS: The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.

Warimwe GM, Fletcher HA, Olotu A, Agnandji ST, Hill AVS, Marsh K, Bejon P. 2013. Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data. BMC Med, 11 (1), pp. 184. | Show Abstract | Read more

BACKGROUND: RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa. METHODS: Of 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling. RESULTS: The unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset. CONCLUSION: The results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00380393 and NCT00436007.

Warimwe GM, Recker M, Kiragu EW, Buckee CO, Wambua J, Musyoki JN, Marsh K, Bull PC. 2013. Plasmodium falciparum var gene expression homogeneity as a marker of the host-parasite relationship under different levels of naturally acquired immunity to malaria. PLoS One, 8 (7), pp. e70467. | Show Abstract | Read more

Acquired immunity to Plasmodium falciparum infection causes a change from frequent, sometimes life-threatening, malaria in young children to asymptomatic, chronic infections in older children and adults. Little is known about how this transition occurs but antibodies to the extremely diverse PfEMP1 parasite antigens are thought to play a role. PfEMP1 is encoded by a family of 60 var genes that undergo clonal antigenic variation, potentially creating an antigenically heterogeneous infecting population of parasites within the host. Previous theoretical work suggests that antibodies to PfEMP1 may play a role in "orchestrating" their expression within infections leading to sequential, homogeneous expression of var genes, and prolonged infection chronicity. Here, using a cloning and sequencing approach we compare the var expression homogeneity (VEH) between isolates from children with asymptomatic and clinical infections. We show that asymptomatic infections have higher VEH than clinical infections and a broader host antibody response. We discuss this in relation to the potential role of host antibodies in promoting chronicity of infection and parasite survival through the low transmission season.

Warimwe GM, Murungi LM, Kamuyu G, Nyangweso GM, Wambua J, Naranbhai V, Fletcher HA, Hill AVS, Bejon P, Osier FHA, Marsh K. 2013. The ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in Kenyan children. PLoS One, 8 (2), pp. e57320. | Show Abstract | Read more

BACKGROUND: Plasmodium falciparum malaria remains a major cause of illness and death in sub-Saharan Africa. Young children bear the brunt of the disease and though older children and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P. falciparum infection. A better understanding of the host factors associated with immunity to clinical malaria and the ability to sustain asymptomatic P. falciparum infection will aid the development of improved strategies for disease prevention. METHODS AND FINDINGS: Here we investigate whether full differential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled at five annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured in peripheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up. This association is evident among children with asymptomatic P. falciparum infection at the time the cell counts are measured (Hazard ratio (HR)  =  2.7 (95% CI 1.42, 5.01, P  =  0.002) but not in those without detectable parasitaemia (HR  =  1.0 (95% CI 0.74, 1.42, P  =  0.9). CONCLUSIONS: We propose that the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts, reflects an individual's capacity to mount an effective immune response to P. falciparum infection.

Chan J-A, Howell KB, Reiling L, Ataide R, Mackintosh CL, Fowkes FJI, Petter M, Chesson JM, Langer C, Warimwe GM et al. 2012. Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity. J Clin Invest, 122 (9), pp. 3227-3238. | Show Abstract | Read more

Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

Warimwe GM, Fegan G, Musyoki JN, Newton CRJC, Opiyo M, Githinji G, Andisi C, Menza F, Kitsao B, Marsh K, Bull PC. 2012. Prognostic indicators of life-threatening malaria are associated with distinct parasite variant antigen profiles. Sci Transl Med, 4 (129), pp. 129ra45. | Show Abstract | Read more

PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called "group A" in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the var genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A-like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population.

Warimwe GM, Keane TM, Fegan G, Musyoki JN, Newton CRJC, Pain A, Berriman M, Marsh K, Bull PC. 2009. Plasmodium falciparum var gene expression is modified by host immunity. Proc Natl Acad Sci U S A, 106 (51), pp. 21801-21806. | Show Abstract | Read more

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a potentially important family of immune targets, which play a central role in the host-parasite interaction by binding to various host molecules. They are encoded by a diverse family of genes called var, of which there are approximately 60 copies in each parasite genome. In sub-Saharan Africa, although P. falciparum infection occurs throughout life, severe malarial disease tends to occur only in childhood. This could potentially be explained if (i) PfEMP1 variants differ in their capacity to support pathogenesis of severe malaria and (ii) this capacity is linked to the likelihood of each molecule being recognized and cleared by naturally acquired antibodies. Here, in a study of 217 Kenyan children with malaria, we show that expression of a group of var genes "cys2," containing a distinct pattern of cysteine residues, is associated with low host immunity. Expression of cys2 genes was associated with parasites from young children, those with severe malaria, and those with a poorly developed antibody response to parasite-infected erythrocyte surface antigens. Cys-2 var genes form a minor component of all genomic var repertoires analyzed to date. Therefore, the results are compatible with the hypothesis that the genomic var gene repertoire is organized such that PfEMP1 molecules that confer the most virulence to the parasite tend also to be those that are most susceptible to the development of host immunity. This may help the parasite to adapt effectively to the development of host antibodies through modification of the host-parasite relationship.

Bejon P, Warimwe G, Mackintosh CL, Mackinnon MJ, Kinyanjui SM, Musyoki JN, Bull PC, Marsh K. 2009. Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure. Infect Immun, 77 (5), pp. 1917-1923. | Show Abstract | Read more

In studies of immunity to malaria, the absence of febrile malaria is commonly considered evidence of "protection." However, apparent "protection" may be due to a lack of exposure to infective mosquito bites or due to immunity. We studied a cohort that was given curative antimalarials before monitoring began and documented newly acquired asymptomatic parasitemia and febrile malaria episodes during 3 months of surveillance. With increasing age, there was a shift away from febrile malaria to acquiring asymptomatic parasitemia, with no change in the overall incidence of infection. Antibodies to the infected red cell surface were associated with acquiring asymptomatic infection rather than febrile malaria or remaining uninfected. Bed net use was associated with remaining uninfected rather than acquiring asymptomatic infection or febrile malaria. These observations suggest that most uninfected children were unexposed rather than "immune." Had they been immune, we would have expected the proportion of uninfected children to rise with age and that the uninfected children would have been distinguished from children with febrile malaria by the protective antibody response. We show that removing the less exposed children from conventional analyses clarifies the effects of immunity, transmission intensity, bed nets, and age. Observational studies and vaccine trials will have increased power if they differentiate between unexposed and immune children.

Kyriacou HM, Steen KE, Raza A, Arman M, Warimwe G, Bull PC, Havlik I, Rowe JA. 2007. In vitro inhibition of Plasmodium falciparum rosette formation by Curdlan sulfate. Antimicrob Agents Chemother, 51 (4), pp. 1321-1326. | Show Abstract | Read more

Spontaneous binding of infected erythrocytes to uninfected erythrocytes to form rosettes is a property of some strains of Plasmodium falciparum that is linked to severe complications of malaria. Curdlan sulfate (CRDS) is a sulfated glycoconjugate compound that is chemically similar to known rosette-inhibiting drugs such as heparin. CRDS has previously been shown to have antimalarial activity in vitro and is safe for clinical use. Here we show that CRDS at therapeutic levels (10 to 100 microg/ml) significantly reduces rosette formation in vitro in seven P. falciparum laboratory strains and in a group of 18 African clinical isolates. The strong ability to inhibit rosetting suggests that CRDS has the potential to reduce the severe complications and mortality rates from P. falciparum malaria among African children. Our data support further clinical trials of CRDS.

Verra F, Simpore J, Warimwe GM, Tetteh KK, Howard T, Osier FHA, Bancone G, Avellino P, Blot I, Fegan G et al. 2007. Haemoglobin C and S role in acquired immunity against Plasmodium falciparum malaria. PLoS One, 2 (10), pp. e978. | Show Abstract | Read more

A recently proposed mechanism of protection for haemoglobin C (HbC; beta6Glu-->Lys) links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA) encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i) total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS); ii) total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii) total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the beta-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria.

Munster VJ, Wells D, Lambe T, Wright D, Fischer RJ, Bushmaker T, Saturday G, van Doremalen N, Gilbert SC, de Wit E, Warimwe GM. 2017. Protective efficacy of a novel simian adenovirus vaccine against lethal MERS-CoV challenge in a transgenic human DPP4 mouse model. NPJ Vaccines, 2 (1), pp. 28. | Show Abstract | Read more

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic virus that causes severe respiratory disease in humans with a case fatality rate close to 40%, but for which no vaccines are available. Here, we evaluated the utility of ChAdOx1, a promising replication-deficient simian adenovirus vaccine vector platform with an established safety profile in humans and dromedary camels, for MERS-CoV vaccine development. Using a transgenic lethal BALB/c MERS-CoV mouse model we showed that single dose intranasal or intramuscular immunisation with ChAdOx1 MERS, encoding full-length MERS-CoV Spike glycoprotein, is highly immunogenic and confers protection against lethal viral challenge. Immunogenicity and efficacy were comparable between immunisation routes. Together these data provide support for further evaluation of ChAdOx1 MERS vaccine in humans and dromedary camels, the animal reservoir of infection.

Gilbert SC, Warimwe GM. 2017. Rapid development of vaccines against emerging pathogens: The replication-deficient simian adenovirus platform technology. Vaccine, 35 (35 Pt A), pp. 4461-4464. | Show Abstract | Read more

Despite the fact that there had been multiple small outbreaks of Ebola Virus Disease, when a large outbreak occurred in 2014 there were no vaccines or drugs available for use. Clinical development of multiple candidate vaccines was then initiated in parallel with attempts to contain the outbreak but only one vaccine was eventually tested in a phase III trial. In order to be better prepared for future outbreaks of known human pathogens, platform technologies to accelerate vaccine development should be employed, allowing vaccine developers to take advantage of detailed knowledge of the vaccine platform and facilitating rapid progress to clinical trials and eventually to vaccine stockpiles. This review gives an example of one such vaccine platform, replication-deficient simian adenoviruses, and describes progress in human and livestock vaccine development for three outbreak pathogens, Ebola virus, Rift Valley Fever Virus and Middle East Respiratory Syndrome Coronavirus.

Alharbi NK, Padron-Regalado E, Thompson CP, Kupke A, Wells D, Sloan MA, Grehan K, Temperton N, Lambe T, Warimwe G et al. 2017. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine, 35 (30), pp. 3780-3788. | Show Abstract | Read more

The Middle East respiratory syndrome coronavirus (MERS-CoV) has infected more than 1900 humans, since 2012. The syndrome ranges from asymptomatic and mild cases to severe pneumonia and death. The virus is believed to be circulating in dromedary camels without notable symptoms since the 1980s. Therefore, dromedary camels are considered the only animal source of infection. Neither antiviral drugs nor vaccines are approved for veterinary or medical use despite active research on this area. Here, we developed four vaccine candidates against MERS-CoV based on ChAdOx1 and MVA viral vectors, two candidates per vector. All vaccines contained the full-length spike gene of MERS-CoV; ChAdOx1 MERS vaccines were produced with or without the leader sequence of the human tissue plasminogen activator gene (tPA) where MVA MERS vaccines were produced with tPA, but either the mH5 or F11 promoter driving expression of the spike gene. All vaccine candidates were evaluated in a mouse model in prime only or prime-boost regimens. ChAdOx1 MERS with tPA induced higher neutralising antibodies than ChAdOx1 MERS without tPA. A single dose of ChAdOx1 MERS with tPA elicited cellular immune responses as well as neutralising antibodies that were boosted to a significantly higher level by MVA MERS. The humoral immunogenicity of a single dose of ChAdOx1 MERS with tPA was equivalent to two doses of MVA MERS (also with tPA). MVA MERS with mH5 or F11 promoter induced similar antibody levels; however, F11 promoter enhanced the cellular immunogenicity of MVA MERS to significantly higher magnitudes. In conclusion, our study showed that MERS-CoV vaccine candidates could be optimized by utilising different viral vectors, various genetic designs of the vectors, or different regimens to increase immunogenicity. ChAdOx1 and MVA vectored vaccines have been safely evaluated in camels and humans and these MERS vaccine candidates should now be tested in camels and in clinical trials.

Dulal P, Wright D, Ashfield R, Hill AVS, Charleston B, Warimwe GM. 2016. Potency of a thermostabilised chimpanzee adenovirus Rift Valley Fever vaccine in cattle. Vaccine, 34 (20), pp. 2296-2298. | Show Abstract | Read more

Development of safe and efficacious vaccines whose potency is unaffected by long-term storage at ambient temperature would obviate major vaccine deployment hurdles and limit wastage associated with breaks in the vaccine cold chain. Here, we evaluated the immunogenicity of a novel chimpanzee adenovirus vectored Rift Valley Fever vaccine (ChAdOx1-GnGc) in cattle, following its thermostabilisation by slow desiccation on glass fiber membranes in the non-reducing sugars trehalose and sucrose. Thermostabilised ChAdOx1-GnGc vaccine stored for 6 months at 25, 37 or 45 ° C elicited comparable Rift Valley Fever virus neutralising antibody titres to those elicited by the 'cold chain' vaccine (stored at -80 ° C throughout) at the same dose, and these were within the range associated with protection against Rift Valley Fever in cattle. The results support the use of sugar-membrane thermostabilised vaccines in target livestock species.

Warimwe GM, Abdi AI, Muthui M, Fegan G, Musyoki JN, Marsh K, Bull PC. 2016. Serological Conservation of Parasite-Infected Erythrocytes Predicts Plasmodium falciparum Erythrocyte Membrane Protein 1 Gene Expression but Not Severity of Childhood Malaria. Infect Immun, 84 (5), pp. 1331-1335. | Show Abstract | Read more

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), expressed on P. falciparum-infected erythrocytes, is a major family of clonally variant targets of naturally acquired immunity to malaria. Previous studies have demonstrated that in areas where malaria is endemic, antibodies to infected erythrocytes from children with severe malaria tend to be more seroprevalent than antibodies to infected erythrocytes from children with nonsevere malaria. These data have led to a working hypothesis that PfEMP1 variants associated with parasite virulence are relatively conserved in structure. However, the longevity of such serologically conserved variants in the parasite population is unknown. Here, using infected erythrocytes from recently sampled clinical P. falciparum samples, we measured serological conservation using pools of antibodies in sera that had been sampled 10 to 12 years earlier. The serological conservation of infected erythrocytes strongly correlated with the expression of specific PfEMP1 subsets previously found to be associated with severe malaria. However, we found no association between serological conservation per se and disease severity within these data. This contrasts with the simple hypothesis that P. falciparum isolates with a serologically conserved group of PfEMP1 variants cause severe malaria. The data are instead consistent with periodic turnover of the immunodominant epitopes of PfEMP1 associated with severe malaria.

Warimwe GM, Gesharisha J, Carr BV, Otieno S, Otingah K, Wright D, Charleston B, Okoth E, Elena L-G, Lorenzo G et al. 2016. Chimpanzee Adenovirus Vaccine Provides Multispecies Protection against Rift Valley Fever. Sci Rep, 6 (1), pp. 20617. | Show Abstract | Read more

Rift Valley Fever virus (RVFV) causes recurrent outbreaks of acute life-threatening human and livestock illness in Africa and the Arabian Peninsula. No licensed vaccines are currently available for humans and those widely used in livestock have major safety concerns. A 'One Health' vaccine development approach, in which the same vaccine is co-developed for multiple susceptible species, is an attractive strategy for RVFV. Here, we utilized a replication-deficient chimpanzee adenovirus vaccine platform with an established human and livestock safety profile, ChAdOx1, to develop a vaccine for use against RVFV in both livestock and humans. We show that single-dose immunization with ChAdOx1-GnGc vaccine, encoding RVFV envelope glycoproteins, elicits high-titre RVFV-neutralizing antibody and provides solid protection against RVFV challenge in the most susceptible natural target species of the virus-sheep, goats and cattle. In addition we demonstrate induction of RVFV-neutralizing antibody by ChAdOx1-GnGc vaccination in dromedary camels, further illustrating the potency of replication-deficient chimpanzee adenovirus vaccine platforms. Thus, ChAdOx1-GnGc warrants evaluation in human clinical trials and could potentially address the unmet human and livestock vaccine needs.

Abdi AI, Warimwe GM, Muthui MK, Kivisi CA, Kiragu EW, Fegan GW, Bull PC. 2016. Global selection of Plasmodium falciparum virulence antigen expression by host antibodies. Sci Rep, 6 (1), pp. 19882. | Show Abstract | Read more

Parasite proteins called PfEMP1 that are inserted on the surface of infected erythrocytes, play a key role in the severe pathology associated with infection by the Plasmodium falciparum malaria parasite. These proteins mediate binding of infected cells to the endothelial lining of blood vessels as a strategy to avoid clearance by the spleen and are major targets of naturally acquired immunity. PfEMP1 is encoded by a large multi-gene family called var. Mutually-exclusive transcriptional switching between var genes allows parasites to escape host antibodies. This study examined in detail the patterns of expression of var in a well-characterized sample of parasites from Kenyan Children. Instead of observing clear inverse relationships between the expression of broad sub-classes of PfEMP1, we found that expression of different PfEMP1 groups vary relatively independently. Parasite adaptation to host antibodies also appears to involve a general reduction in detectable var gene expression. We suggest that parasites switch both between different PfEMP1 variants and between high and low expression states. Such a strategy could provide a means of avoiding immunological detection and promoting survival under high levels of host immunity.

Lorenzo G, López-Gil E, Warimwe GM, Brun A. 2015. Understanding Rift Valley fever: contributions of animal models to disease characterization and control. Mol Immunol, 66 (1), pp. 78-88. | Show Abstract | Read more

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis with devastating health impacts in domestic ruminants and humans. Effective vaccines and accurate disease diagnostic tools are key components in the control of RVF. Animal models reproducing infection with RVF virus are of upmost importance in the development of these disease control tools. Rodent infection models are currently used in the initial steps of vaccine development and for the study of virus induced pathology. Translation of data obtained in these animal models to target species (ruminants and humans) is highly desirable but does not always occur. Small ruminants and non-human primates have been used for pathogenesis and transmission studies, and for testing the efficacy of vaccines and therapeutic antiviral compounds. However, the molecular mechanisms of the immune response elicited by RVF virus infection or vaccination are still poorly understood. The paucity of data in this area offers opportunities for new research activities and programs. This review summarizes our current understanding with respect to immunity and pathogenesis of RVF in animal models with a particular emphasis on small ruminants and non-human primates, including recent experimental infection data in sheep.

Busquets N, Lorenzo G, López-Gil E, Rivas R, Solanes D, Galindo-Cardiel I, Abad FX, Rodríguez F, Bensaid A, Warimwe G et al. 2014. Efficacy assessment of an MVA vectored Rift Valley Fever vaccine in lambs. Antiviral Res, 108 (1), pp. 165-172. | Show Abstract | Read more

The present study has evaluated the protection conferred by a single subcutaneous dose of a modified vaccinia virus Ankara (MVA) vectored vaccine encoding the Rift Valley Fever virus (RVFV) glycoproteins Gn and Gc in lambs. Three groups of six to seven lambs were immunized as follows: one group received the vaccine (termed rMVA-GnGc), a second group received an MVA vector (vector control) and a third group received saline solution (non-vaccinated control). Fourteen days later, all animals were subcutaneously challenged with 10(5) TCID50 of the virulent RVFV isolate 56/74 and vaccine efficacy assessed using standard endpoints. Two lambs (one from the vaccine group and one from the vector control group) succumbed to RVFV challenge, showing characteristic liver lesions. Lambs from both the vector control and non-vaccinated groups were febrile from days 2 to 5 post challenge (pc) while those in the rMVA-GnGc group showed a single peak of pyrexia at day 3 pc. RVFV RNA was detected in both nasal and oral swabs from days 3 to 7 pc in some lambs from the vector control and non-vaccinated groups, but no viral shedding could be detected in the surviving lambs vaccinated with rMVA-GnGc. Together, the data suggest that a single dose of the rMVA-GnGc vaccine may be sufficient to reduce RVFV shedding and duration of viremia but does not provide sterile immunity nor protection from disease. Further optimization of this vaccine approach in lambs is warranted.

Warimwe GM, Lorenzo G, Lopez-Gil E, Reyes-Sandoval A, Cottingham MG, Spencer AJ, Collins KA, Dicks MDJ, Milicic A, Lall A et al. 2013. Immunogenicity and efficacy of a chimpanzee adenovirus-vectored Rift Valley fever vaccine in mice. Virol J, 10 (1), pp. 349. | Show Abstract | Read more

BACKGROUND: Rift Valley Fever (RVF) is a viral zoonosis that historically affects livestock production and human health in sub-Saharan Africa, though epizootics have also occurred in the Arabian Peninsula. Whilst an effective live-attenuated vaccine is available for livestock, there is currently no licensed human RVF vaccine. Replication-deficient chimpanzee adenovirus (ChAd) vectors are an ideal platform for development of a human RVF vaccine, given the low prevalence of neutralizing antibodies against them in the human population, and their excellent safety and immunogenicity profile in human clinical trials of vaccines against a wide range of pathogens. METHODS: Here, in BALB/c mice, we evaluated the immunogenicity and efficacy of a replication-deficient chimpanzee adenovirus vector, ChAdOx1, encoding the RVF virus envelope glycoproteins, Gn and Gc, which are targets of virus neutralizing antibodies. The ChAdOx1-GnGc vaccine was assessed in comparison to a replication-deficient human adenovirus type 5 vector encoding Gn and Gc (HAdV5-GnGc), a strategy previously shown to confer protective immunity against RVF in mice. RESULTS: A single immunization with either of the vaccines conferred protection against RVF virus challenge eight weeks post-immunization. Both vaccines elicited RVF virus neutralizing antibody and a robust CD8+ T cell response. CONCLUSIONS: Together the results support further development of RVF vaccines based on replication-deficient adenovirus vectors, with ChAdOx1-GnGc being a potential candidate for use in future human clinical trials.

Naranbhai V, Hill AVS, Abdool Karim SS, Naidoo K, Abdool Karim Q, Warimwe GM, McShane H, Fletcher H. 2014. Ratio of monocytes to lymphocytes in peripheral blood identifies adults at risk of incident tuberculosis among HIV-infected adults initiating antiretroviral therapy. J Infect Dis, 209 (4), pp. 500-509. | Show Abstract | Read more

BACKGROUND: Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the "ML ratio") was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases. METHODS: The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted. RESULTS: The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38-61.54), 16.36 (95% CI, 12.39-21.23), and 51.80 (95% CI, 23.10-101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4(+) T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39-4.40; P = .002). CONCLUSIONS: The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.

Warimwe GM, Fletcher HA, Olotu A, Agnandji ST, Hill AVS, Marsh K, Bejon P. 2013. Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data. BMC Med, 11 (1), pp. 184. | Show Abstract | Read more

BACKGROUND: RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa. METHODS: Of 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling. RESULTS: The unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset. CONCLUSION: The results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00380393 and NCT00436007.

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