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HIV & HIV-associated infections
Neglected infectious diseases
Making the case for typhoid fever vaccination
The THECA study will provide important evidence on the impact of typhoid fever vaccination in Africa.
The DRC study will more closely simulate real-world conditions, like those of country-wide vaccine intro-ductions.
Typhoid fever, caused by infection with Salmonella typhi, affects around 22 million people every year, causing more than 200,000 deaths. Typhoid fever is most commonly found in low-income countries where access to clean water and/or adequate sanitation infrastructure is lacking. African countries are at particular risk of typhoid fever outbreaks.
Typhoid fever can be treated effectively with antibiotics but in many countries growing rates of bacterial resistance to antibiotics are reducing the number of effective and viable treatment options. In addition, rapid urbanisation and climate change effects put additional pressure on already-strained water and sanitation systems. This increases the risk of typhoid fever transmission in the total population.
Therefore, vaccines are critical to the prevention and control of typhoid fever. Although vaccines against typhoid have existed since the late 19th century, early generation vaccines have major limitations precluding widespread use. Dr Florian Marks of the University of Cambridge, United Kingdom, coordinates the THECA study, which is part of an effort to study one of a novel class of typhoid conjugate vaccines. The Typbar-TCV® vaccine has been licensed despite limited data on its efficacy. The Bill & Melinda Gates Foundation is supporting the TyVAC study, which consists of three trials – two in Asia and one in Malawi – to generate additional evidence on safety and efficacy.
Dr Marks: “This novel class of typhoid conjugate vaccines is poised to supplant all existing vaccines by demonstrating longer-lasting effectiveness and covering a broader proportion of the at-risk population including infants as young as six months of age.”
Dr Florian Marks
The THECA study will provide policymakers in Africa with additional data on the safety and efficacy of Typbar-TCV® and on its performance in real-life settings and factors that affect its effectiveness in practice. This will enable them to make better-informed decisions on whether to introduce the vaccine and how to use it.
Dr Marks: “The vaccine could not only prevent typhoid fever and thus reduce mortality and morbidity. It will also lessen the reliance on antibiotics which currently are the cornerstone of typhoid fever control. This is critical in view of the high case-fatality rate of typhoid in the presence of antimicrobial resistance. The outcomes of this study will be transferrable to other countries. These data could strengthen the case for the introduction of this typhoid conjugate vaccine in countries eligible for GAVI support and inform optimal strategies for their deployment.
“Typbar-TCV® was the first typhoid conjugate vaccine to achieve WHO-prequalification in early 2018 based on immunogenicity data and in the light of further assessment. For successful typhoid conjugate vaccine introductions into countries eligible for GAVI support, additional data are needed. These data regard long-term safety, immunogenicity, clinical efficacy, effectiveness (i.e. population-level protection - direct and herd), and cost-effectiveness. These characteristics need to be assessed in large-scale projects”.
Photo: THECA project team members visiting the Health Centre director and healthcare workers at the Juansa Health Centre in the Asante Akim North Municipality.
Project at a glance
Project: THECA study
Project lead: Dr Florian Marks, University of Cambridge, UK
Countries involved: Bangladesh, Belgium, Burkina Faso, Democratic Republic of the Congo, France, Ghana, Republic of Korea, Madagascar, United Kingdom and the United States
Target population(s): Children
Year awarded: 2018
EDCTP funding: €13 M
Total project funding: €35 M
The THECA study complements the trials funded by the Gates Foundation by conducting two additional studies in Ghana and the Democratic Republic of the Congo (DRC). “These studies will generate important vaccine performance data from field sites in areas where typhoid fever is endemic while being collected under strict clinical trial conditions,” says Dr Marks.
The Ghana study is a randomised controlled trial that will generate data on safety and efficacy and population-level protection, adding to the pool of African data provided by the Malawi trial.
The DRC study, by contrast, will be embedded within a mass vaccination campaign, with a case-control design used to assess efficacy. This study will provide additional data on protection when the vaccine is used within routine public health systems, as well as valuable insight into the feasibility and cost-effectiveness of its use.
Dr Marks: “The Ghana trial will provide comparable vaccine evaluations to the TyVAC trials in an unexamined region of Africa. Importantly, the study in DRC will more closely simulate “real-world” conditions in order to generate data based on methods resembling those that will ultimately be used in country-wide vaccine introductions.”
“Like the TyVAC study, THECA will also play a role in working with stakeholders in countries to assess the incidence of the disease, the age distribution of the burden and its geographic distribution. This will help to inform decision-making on the introduction of typhoid conjugate vaccines and subsequent vaccination strategies. The THECA and TyVAC consortia are working closely together to ensure that our efforts are coordinated.”
Photo: THECA project team members visiting the hospital director and healthcare workers at the Konongo-Odumase Government Hospital in the Asante Akim Central Municipality.
A four-strike vaccine against malaria
With encouraging progress in malaria vaccine development, the Multi-Stage Malaria Vaccine Consortium (MMVC) will test a novel vaccine combination targeting four stages of the malaria parasite life cycle.
MMVC now includes further African research groups and new industrial partners.
The malaria parasite has a complex life cycle, spanning mosquitoes and humans. When injected into the bloodstream following the bite of an infected mosquito, it first invades and multiplies within liver cells, before seeking refuge and multiplying again in red blood cells. When these burst parasites circulating in the bloodstream can be taken up by a feeding mosquito.
Although only a single cell, the parasite is a master of disguise, adopting entirely different forms at different stages of its life cycle. Malaria vaccine developers typically focus on one specific stage of the life cycle. The only licensed malaria vaccine, RTS,S, targets the initial human stage, to prevent liver infection. However, a vaccine targeting the final bloodstream stage could block transmission to mosquitoes.
Professor Adrian Hill of the University of Oxford, United Kingdom: “Approaches that used whole parasites, yielded candidate vaccines which are very expensive to produce and have shown only modest efficacy in Africa and none in young children. So, the most advanced efforts have been on sub-unit vaccines. Fortunately, there is now an active clinical development of new vaccines against all four stages of the malaria parasite’s life cycle”.
Prof. Adrian Hill
The project will generate key evidence on the efficacy of the four-stage vaccine, with the aim of achieving the WHO Roadmap’s target of 75% efficacy. Such a vaccine could make a major contribution to reducing the incidence of an infection that still kills more than 1000 children every day.
“The goal of this consortium is to develop the first high-efficacy multi-component vaccine against malaria. The primary impact in the late 2020s should be to reduce significantly the high rates of clinical malaria and malarial deaths in infants and children in many African countries. Thereafter, this vaccine will contribute to ongoing efforts to reduce transmission of malaria leading progressively to elimination and eventual malaria eradiation,” says Prof. Hill.
Photo: MMVC annual meeting Dakar 2018.
In view of the exciting progress being made in vaccine development at all stages of the life cycle – pre-liver, liver, red blood cell and bloodstream stages – the MMVC consortium has ambitious plans to combine them in a single formulation, maximising the benefits of the individual vaccines.
Prof. Hill, who leads the MMVC project, explains: “What is unique about the current project is that for the first time the aim is to develop a vaccine against multiple life cycle stages, which includes three very different vaccine candidates that have already shown efficacy in clinical trials.”
The vaccine candidate includes a next-generation version of RTS,S, known as R21; a liver-stage vaccine that has shown positive results in EDCTP-funded trials; a promising vaccine targeting a key protein involved in red blood cell invasion, PfRH5; and a vaccine targeting a key protein in the final bloodstream form, Pfs25.
A series of controlled human infection studies – using new capacity in Africa – and pilot trials will inform the design of an appropriate vaccination strategy. This will then be tested in a phase II trial in infants in sites with different levels of malaria transmission. The project will also build capacity to test the vaccine in adults as a possible way of blocking transmission to mosquitoes in malaria elimination campaigns.
Prof. Hill: “The current project builds upon the success of the earlier MVVC consortium, funded under the first EDCTP programme. Many of the partners are the same but we now also include further research groups in Africa – in Burkina Faso, Sierra Leone and Tanzania – and new industrial partners: the Serum Institute of India, Novavax AB and Janssen. Moreover, in addition to the liver-stage vaccines developed in MVVC we now also test protein-in-adjuvant vaccines targeting the sporozoite, blood-stage and sexual stages of the life-cycle“.
Project at a glance
Project: Multi-Stage Malaria Vaccine Consortium
Project lead: Professor Adrian Hill, University of Oxford, UK
Countries involved: Burkina Faso, France,India, Kenya, the Netherlands, Sierra Leone,Sweden,Tanzania
Target population(s): Infants
Sample size: 1493 (estimated for four trials)
Year funded: 2018
EDCTP funding: €15 M
Total project funding: €20 M
Photo: The malaria vaccination team, Nanoro, Burkina Faso
Photo: MVVC filed activities at the Nanoro vaccine trial site, Burkina Faso.
Photo: Infant being administered malaria vaccine, Nanoro, Burkina Faso.
Making the yellow fever vaccine go further
The NIFTY trial will determine whether smaller doses of yellow fever vaccine stimulate protective immune responses, so more people could benefit from a vaccine in limited supply.
The NIFTY trial will generate the data on fractional dosing for adults and children that will guide policy making.
Yellow fever has shown a resurgence in recent years. It affects 34 countries in Africa, causing up to 170,000 cases and 60,000 deaths a year. A safe and highly effective vaccine is available, but it is difficult to manufacture and shortages in supply contribute to limiting routine immunisation and adequate stockpiling to deal with major outbreaks.
“The main challenge is a global shortage of yellow fever vaccine,” says Dr George Warimwe of the University of Oxford, United Kingdom. “We simply do not produce enough vaccine to meet the demand for routine immunisation, and while a yellow fever vaccine stockpile is reserved for control of outbreaks, it is frequently depleted. Increasing the global supply of the vaccine would ensure that the vaccine is always available for use in at-risk populations in Africa and elsewhere. This, together with surveillance for early detection of yellow fever outbreaks, would sustainably control yellow fever in Africa and elsewhere.”
Dr George Warimwe
In 2015, UNICEF estimated that global demand for the yellow fever vaccine was more than 40% higher than supply. Fractional dosing could enable more individuals to receive a potentially life-saving vaccine, but only if vaccine effectiveness is not compromised. The NIFTY trial will generate key data to answer this question.
The NIFTY trial will generate key data on fractional dosing of yellow fever vaccine in adults and children to guide policy making. Dr Warimwe who leads the NIFTY trial, says: “It is essential that we make the best possible use of the available vaccine stock. However, the actual minimal dose of vaccine needed to elicit an effective immune response has not been determined. This is the focus of our study.”
Immune responses will be monitored in nearly 2000 adults vaccinated with the full dose and three fractional doses of decreasing volume. The lowest fractional dose generating protective responses in adults will then be compared with the full dose in 700 children. Immune responses will be evaluated after one month and after one year.
Dr Warimwe: “The immune response stimulated by the standard dose will be compared to three doses that are orders of magnitude lower. Should we find that the lower vaccine doses are able to generate comparable immune responses to the standard dose, this could lead to a substantial increase in the number of doses that can be given based on the world’s currently available vaccine stock.”
Project at a glance
Project: Non-inferiority of Fractional Doses Trial forYellow Fever Vaccine (NIFTY)
Project lead: Dr George Warimwe, University of Oxford, Male, UK
Countries involved: France, Kenya, Senegal, Uganda, the UK
Target population(s): Adults; children
Sample size: 1935 adults; 700 children (targets)
Year funded: 2018
EDCTP funding: €3.2 M
To address the supply shortage, WHO recently recommended the use of ‘fractional dosing’ – using one-fifth of the standard vaccine dose – in emergency outbreak situations. This is thought to be appropriate as studies have shown that even fractional doses stimulate immune responses in excess of those thought to provide protection from infection.
Dr Warimwe: “Our study will provide data on the ability of low vaccine doses to generate protective immune responses against the yellow fever virus. A positive result may enhance our ability to meet the three key objectives of the WHO’s ‘Eliminate Yellow Fever Epidemics’ Strategy: protect at-risk populations, prevent the global spread of the disease, and contain outbreaks rapidly“.
Photo: The NIFTY team in Kenya.
Photo: The NIFTY team conducting community sensitisation.
CAP012 SAMBA Trial:
A new approach to HIV prevention
Passive immunisation with broadly neutralising antibodies could offer a novel way to block HIV infection.
The project builds on the discovery of a lineage of broadly neutralising antibodies in a woman from KwaZulu Natal.
HIV is a highly diverse and rapidly evolving pathogen. Despite many efforts, a vaccine that would protect against multiple HIV variants has yet to be developed, threatening global efforts to bring the HIV/AIDS epidemic under control by 2030.
“Although there have been major advances in understanding HIV pathogenesis and the human immune system over the past three decades that continue to contribute to HIV vaccine development, several unique challenges remain before an effective vaccine will be developed”, explains Professor Salim S. Abdool Karim of the Centre for the Aids Programme of Research in South Africa (CAPRISA).
For a vaccine to be effective at a global level, it would have to protect against many evolving and diverse strains of HIV. Interestingly, a small number of individuals worldwide have been found to produce ‘broadly neutralising antibodies’ – antibodies that recognise structures common across many HIV strains. “There are hopes that these antibodies could be mass-produced and used in passive immunisation, that is be given to people periodically to protect against infection”, says Prof. Karim.
Professor Salim S. Abdool Karim
The CAP012 SAMBA project could advance the development of a radically new approach to HIV prevention. It offers the prospect of HIV protection delivered through injections every four to six months. This approach would be of particular benefit to women. Therefore, the antibodies are being evaluated in groups of women. However, a positive signal from the CAPRISA 012 trial will lead to parallel research and development paths for both men and women Long-acting injectable bNAbs for passive immunisation mark a direction distinct from current and recently tested PrEP strategies.
Prof. Karim: “In the global landscape, if this trial shows efficacy, it could have a marked impact on global research in HIV prevention. It will signal a shift from the current limitations of antiretroviral-based tablets, gels, injectables and rings to a long-lasting HIV prevention strategy. Further, if the bNAb combinations identified in this study are found to be effective in preventing HIV, their target epitopes will be good candidates for vaccine development”.
“This innovative PrEP approach, if effective, could offer young women, who are unable to negotiate safer sex, a technology to remain HIV free. This technology has several key benefits over oral and topical PrEP and also addresses adherence challenges for young women from southern Africa that have led to mixed clinical trial results in the past. More importantly, a widespread immunisation programme can be implemented in public health clinics – reaching millions of people and saving lives.”
Photo: Subcutaneous injection administered by nurses Siyabonga Ximba and Diane Chetty.
Project at a glance
Project: CAP012 SAMBA Trial
Project lead: Professor Salim Abdool Karim, Centre for the AIDS Programme of Research in South Africa, South Africa
Countries involved: France, The Netherlands, South Africa, Zambia
Target population(s): Woman
Year awarded: 2018
EDCTP funding: €9.3 M
The CAP012 SAMBA project builds on the discovery of a lineage of broadly neutralising antibodies, known as CAP256-VRC26.25, in a woman from KwaZulu Natal. The project will analyse the safety of the antibodies in humans, explore their acceptability to potential recipients, and monitor their metabolism in the body. Based on these studies, the most promising combinations of antibodies will be taken forward to a phase II trial to assess safety and efficacy.
Prof. Karim: “These antibodies demonstrated breadth in the number of different strains of HIV they could neutralise, with greater coverage of subtype clade C viruses than other subtypes. One antibody from patient CAPRISA 256, referred to as CAP256-VRC26.25, is among the most potent monoclonal antibodies currently available in the world. The exceptional potency of the CAP256-VRC26 lineage makes them attractive candidates for further testing as preventive or even therapeutic vaccines”.
“The overall goal of the CAPRISA 012 phase I/II trial is to develop a safe and effective long-acting HIV prevention technology, principally for women, based on a combination of anti-HIV monoclonal antibodies. A safe and effective PrEP formulation with bNAbs for women, injectable every four to six months, could have a significant impact on the HIV epidemic in Africa.”
Photo: Study investigators Dr Sharana Mahomed and Dr Nigel Garrett engage with a participant.
Photo: Study member Siphosihle Khanyile meets the partcipant and welcomes her into the clinic.