ASTMH 2020 Annual Meeting (virtual): Day 2
MESA Correspondents bring you cutting-edge coverage from the virtual ASTMH 2020 Annual Meeting
Day 2: Monday, 16th November 2020
Symposium #3: Can We Ignore "Asymptomatic" Low-Density Malaria Any More?
Lucy Okell (Imperial College London, United Kingdom) presented studies to highlight that detecting low-density malaria infections and identifying what factors drive infection in asymptomatic individuals are important elements in malaria elimination. Several studies have shown that low-density infections, undetectable by microscopy, are common in both P. falciparum and P. vivax. These low-density infections require ultrasensitive assays, e.g. qPCR, to be detected. Okell examined the relationship between the past and current transmission intensity in determining the relative abundance of submicroscopic infections in Africa and highlighted that low-density infections prevail in low-transmission areas. Explanations for this latter observation include 1) differences in the age distribution of infected populations with higher prevalence of infection being observed in older age groups in low transmission compared to high transmission settings; 2) low genetic diversity of the parasite in low-transmission settings favouring acquisition of protective immunity in the human population; 3) lower between parasite strains of low-transmission areas, where evolution may favour chronic low-density infections, reducing the parasite’ chances of causing symptoms that require treatment.
Dylan R. Pillai (University of Calgary, Canada) presented work on the changing landscape of malaria diagnostics. For many years, microscopy has been the gold standard for detecting malarial infection, but it comes with various limitations. Rapid diagnostic tests (RDTs) based on immunochromatographic detection of the histidine-rich protein (Hrp) have therefore played a key role in the last two decades. However, the emergence of Hrp2-deleted strains of P. falciparum limits the sensitivity of RDTs. Real-time polymerase chain reaction (PCR) emerged as a far more sensitive and specific tool to detect malaria parasites. PCR is however expensive and may not be applicable in low-income endemic areas. Recently, faster, cheaper and easier to perform loop-mediated isothermal amplification (LAMP) methods have been developed for malaria diagnosis, showing a limit of detection (LOD) of around 0.1 parasites per microliter. Also, it is possible to adapt in-house LAMP protocols enabling visual detection of samples’ positivity, therefore not requiring using of fluorescence readers. Comparison of results obtained with LAMP and qPCR show similar sensitivity of the two methods both in non-endemic and endemic areas. In non-endemic areas, the high negative predictive value of LAMP methods allows to use it as a screening test, with no further examination needed for LAMP negative samples. In endemic areas, LAMP has proven useful in detecting low-density malaria infections in pregnant women, the treatment of which resulted in improved pregnancy outcomes in clinical trials.
Though often ignored, asymptomatic low-density malaria infection plays a crucial role in maintaining transmission of the disease, presenting a setback to global malaria elimination. Gilles Cottrell (Institute of Research for Sustainable Development, France) gave a presentation on the clinical effects of low-density malaria, which often goes undetected (submicroscopic) and causes asymptomatic malaria persisting from a few days to months. Asymptomatic infection could be beneficial by decreasing the risk of malaria illness. However, it also causes anaemia in children and expectant mothers, and moreover, it is associated with low birth-weight. Furthermore, in low-transmission settings, pregnant women are at increased risk of malaria, spontaneous abortions, stillbirths and premature births. Cottrell illustrated that submicroscopic prevalence is higher than microscopic prevalence in pregnant women, with the highest prevalence being detected during the first trimester. Additionally, intermittent preventive treatment in pregnancy (IPTp) does not fully prevent malaria infections, especially submicroscopic low-density infections. Women infected before conception are at higher risk of infection during their pregnancy and maternal infection increases infants’ susceptibility to malaria. Therefore monitoring during the early pregnancy period, or even before conception, is vital for optimal protection of both women and infants. Cottrell envisaged the importance of carrying out longitudinal studies of malaria infection using highly sensitive diagnostic tools to fill the knowledge gaps in low-density asymptomatic malaria.
Fitsum Tadesse (Armauer Hansen Research Institute, Addis Ababa, Ethiopia) illustrated the relationship between asymptomatic malaria and parasite density distributions, gametocyte densities and malaria transmissibility. Especially in low-transmission settings, a large proportion of all malaria infections can be submicroscopic. Moreover, different Plasmodium species produce gametocytes at different rates: P. vivax produces them within 2-3 days, whereas P. falciparum takes 9-12 days. A study with 298 mosquito membrane feeding experiments demonstrated that infectivity positively correlates with parasitemia and gametocytemia. In humans, however, parasitaemia, gametocytemia and mosquito infectivity are correlated in asymptomatic P. falciparum infections but not in clinical malaria cases, where gametocyte carriers were more frequently detected by microscopy among subjects with lower parasite densities. In P. vivax infections, the level of gametocytes mirrors the asexual parasite density, both in symptomatic and asymptomatic infections. In endemic areas, patent P. falciparum infections were approximately three times more infectious than submicroscopic infections. Mosquito membrane feeding assays conducted in four African countries showed that the likelihood of mosquito infection is very low at gametocyte densities below one parasite per microliter and increases steadily from ten parasites per microliter. Therefore, the importance of asymptomatic infections compared to clinical malaria cases in P. falciparum transmission depends on asexual and sexual parasite densities, whereas the relative contribution to the infectious reservoir in a given setting depends on the frequency of asymptomatic infections in the population. Tadesse concludes stressing the importance of conducting longitudinal studies to assess the impact of different factors on parasite biomass kinetics and infectivity.
Plenary Session II COVID-19: Lessons Learned and Future Challenges
Anthony Fauci (National Institutes of Health, United States) started the session with a comprehensive overview of the basic aspects of the SARS-CoV2 infection: virology, transmission, clinical presentation and manifestations of severe COVID-19 disease, social determinants of risk, fundamental public health measures, and therapeutics and vaccines. He described COVID-19 as a pandemic that reached historical proportions not seen in the last hundred years. Fauci further mentioned that if adherence to the main public health response strategies were higher, we would not have seen a resurgence as dramatic as currently happening in the United States and Europe. Towards the end, Fauci described recent events in vaccine development and said he is optimistic that first doses will be administered to priority groups before the end of this year.
John N. Nkengasong (Africa Centres for Disease Control and Prevention, Ethiopia) presented an overview of the COVID-19 response in Africa. The joint continental strategy was preventing transmission, death, and social and economic harm. He named several partnerships and initiatives that played a critical role in the response, such as the partnership to accelerate COVID-19 testing (PACT) in Africa. He further described epidemiological trends across African countries, which increasingly show concerning trends starting in the second half of the year. Key features in Africa's response to COVID-19 were unified leadership, along with a new public health order, partnerships, adaptive development and allocation of public health workers as well as investment in local manufacturing of medical interventions. As the way forward, he emphasized the need to maintain the gains achieved and to be prepared for the second wave in Africa by intensifying public health and social measures against COVID-19, including scale-up of testing and surveillance.
‘The lessons are yet to begin’ was the cautious introduction of Heidi Larson (London School of Hygiene and Tropical Medicine, UK) in her talk on “COVID-19: Lessons Learned and Future Challenges”. She presented results from the Vaccine Confidence Project, which demonstrate the importance of confidence in products, providers, policymakers, and public health systems, in the public's willingness to accept a vaccine. Larson mentioned a wide variety of factors that would contribute to low acceptance and described vaccine hesitancy as a challenge not only in subgroups but also in the wider population. According to Larson, misinformation would be a serious obstacle to the acceptance of a COVID-19 vaccine and could be a ‘tipping point phenomenon’ towards achieving coverage levels required for herd immunity.
In the final talk of the session, Richard Hatchett (Coalition for Epidemic Preparedness Innovations - CEPI, United Kingdom) gave an overview of the role of CEPI in COVID-19 vaccine development and access. In partnership with the leading COVID-19 vaccine developers and non-governmental organizations, CEPI supports funding of nine vaccine candidates, eight of which are in clinical trials. Hatchett described various projects of CEPI that aim to ensure ‘global access to vaccines to all countries at the same time regardless of income’ and current efforts as well as challenges to achieving that goal. In the outlook for the future, Hatchett mentioned that CEPI aims to deliver two billion doses around the world in 2021, and emphasized the need for better preparedness plans for the next pandemic and Disease X, for which their strategy could serve as a model.
Symposium #19: Mechanistic Dose-Response Modelling of Antimalarial Drugs
Joel Tarning (Mahidol Oxford Tropical Medicine Research Unit, Thailand) presented a study on pharmacokinetics (PK) and mosquito-killing effects of ivermectin and its metabolites. Ivermectin showed potent mosquito-killing effects when the mosquitoes (Anopheles dirus and A. minimus) fed on blood from humans who had taken ivermectin, both in membrane feeding and direct feeding assays. Two clinical trials in human volunteers were pooled and analysed using a population PK modelling approach. Bodyweight and co-administration of dihydroartemisinin-piperaquine showed a significant impact on the pharmacokinetic properties of ivermectin. Predicted drug concentrations of ivermectin and its metabolites were linked to mosquito-killing effects and showed substantial differences between mosquito strains. Modelling and simulation suggest potent mosquito-killing effects for over 7 days after a standard 3-day oral dose of ivermectin. The developed model could be a valuable tool to inform dosing policy on transmission blocking and malaria elimination efforts.
Palang Chotsiri (Mahidol Oxford Tropical Medicine Research Unit, Thailand) presented on the topic “Primaquine pharmacokinetics and pharmacodynamics (PK/PD) modelling”. Primaquine is an effective drug for treating P. vivax because of its activity on liver stage parasites. Chotsiri’s presentation showed a population PK/PD modelling approach to predict PK properties of primaquine, and its effect on gametocytes and mosquito infectivity. In the gametocyte dynamics model, Chotsiri showed that primaquine killed gametocytes and higher doses of primaquine resulted in a shorter time to eliminate gametocytes from the blood. Mosquito infectivity was affected by both primaquine and gametocytes, resulting in a lower infectivity at low gametocyte density and high primaquine concentrations. Taken together, this model could be used to determine an optimal primaquine dose for blocking transmission of malaria.
Karen Barnes (University of Cape Town, South Africa) gave a talk focused on improving malaria treatment in vulnerable sub-populations (i.e. pregnant women, infants, hyperparasitaemic patients, or individuals with co-morbidities), which represent an important share of all malaria cases. Antimalarial drugs must be given at optimal dosages to ensure that all patients have an equal chance of being cured; however, during clinical drug development, vulnerable populations are usually excluded. Pooling already existing PK data and conducting individual patient data (IPD) meta-analyses can help to establish adequate dosages in these populations, achieving a sufficient sample size to reach the statistical power needed and increasing validity and generalizability of findings. Currently, this approach is being used to investigate artemisinin combination therapies (ACTs) for treating malnourished children with malaria. Malnourished children were observed to have an increased risk of delayed parasite clearance, recrudescence and re-infection, suggesting suboptimal dosing in this vulnerable population.
Julie Simpson (University of Melbourne, Australia) highlighted the significant declines in efficacy of ACTs in the Greater Mekong Subregion. Using within-host malaria models that capture the interplay between drug concentration and action, the efficacy of combination therapies can be predicted, providing a clinical decision tool for selecting dosing schemes and combination therapies for current and new antimalarials to be evaluated in clinical trials. One case study example is triple ACT (TACT), which combines dihydroartemisinin (DHA) + piperaquine (PPQ) + mefloquine (MQ). An in silico model was used to determine the optimal TACT dosing regimen to achieve ≥90% 42-day cure rates in regions where parasite resistance to DHA-PPQ has emerged. The model predicted the cure rates observed in the TACT clinical trials and is available as an online clinical decision tool (TACT R Shiny App, www.qmalaria.org). Another case study example presented was within-host malaria modelling of the combination therapy OZ439-DSM265, using data from volunteer infection studies, which demonstrated an antagonistic interaction of the combined effect of OZ439-DSM265 and determined the minimum optimal dosing regimens required to achieve a 42-day cure rate ≥90%.
Symposium #20: A Fundamental Way to Prevent Malaria in Pregnancy: Improving Health Outcomes for Pregnant Women and Their Babies One Nurse and Midwife at a Time
Katherine Wolf (Jhpiego, United States) as a symposium organizer highlighted the fifth anniversary of the IPTp Call to Action. While progress has been made, the call is being renewed, particularly as the world faces the COVID-19 pandemic. Health continuity is critical, particularly for expectant mothers in malaria endemic areas. Wolf noted that nurses and midwives are adapting the care they give to pregnant women during COVID-19 to ensure that no pregnant women experience malaria. She invited participants to join the IPTp Call to Action.
Pedro Alonso (World Health Organisation, Switzerland) presented the WHO approach to speed up and scale up the fight against malaria in the pregnant women. WHO’s three-pronged approach is encouraged during pregnancy; including the use of insecticide-treated bed nets to avoid women/vector contact, uptake of sulfadoxine-pyrimethamine (SP) and antimalarial preventive treatment and access to prompt diagnosis and effective treatment. Since 2010, an overall improvement was noted in the number of women who attend antenatal care (ANC) at least once and received malaria intermittent preventive treatment for pregnancy (IPTp). However, there are still barriers, such as transportation, level of education and wealth, which render unacceptable the level of ANC and IPTp coverage. Pregnant women cannot be considered as a forgotten group but a key vulnerable group. Thus, WHO is committed to continuing to put them at the centre of their fight against malaria.
Maud Lugand (Medicine for Malaria Venture, Switzerland) presented on quality measures used in manufacturing medicines used for intermittent preventive treatment for malaria in pregnancy. IPTp is a WHO-recommended intervention, which involves administration of a course of sulfadoxine-pyrimethamine (SP) at each antenatal care visit from the second trimester of pregnancy, as Alonso mentioned before. Its uptake is very low despite being an effective intervention; in 2018, only one third of eligible women in Africa were optimally protected. Sociocultural barriers for low uptake include medical pluralism, low patient acceptance and self-medication. Structural barriers included limited access to ANC services, non-availability of quality-assured SP and low health provider acceptance. MMV supported building GMP production capacity in the region in Nigeria and Kenya, and is currently in the process of developing a user-friendly IPTp-SP package to support local manufacturing companies. They field-tested the packaging to ascertain the use and acceptability, knowledge and perception of it. Results showed women and health care providers had positive experiences with the package.
Aissata Fofana (RTI International, Guinea) shared a study on bringing long-lasting insecticidal nets (LLIN) distribution closer to communities in Guinea through adaptive management, called StopPalu+. This project is to assist the government in reducing malaria-associated morbidity and mortality by helping increase LLIN distribution in the country through monitoring and evaluation. They discovered that distribution points were far and households lost their vouchers for net distribution, therefore the data collected was used to implement the following adaptation measures. Communities were split closer to distribution points, radio spots were used to encourage people to provide their names to get a copy of a voucher for an LLIN, and sensitization activities in schools and group discussions with women and youth associations were held. All these interventions helped increase the expected coverage of LLINs by 20%.
Yacouba Ouedraogo (Jhpiego, Burkina Faso) presented a pilot study on testing the feasibility of community-based IPTp (C-IPTp) provision in Burkina Faso. At only 17-22%, IPTp coverage was low in Burkina Faso in 2014 and 2015,, calling for a high-impact intervention to improve the situation. The study explored whether a community-based approach combined with promotion of routine ANC could increase IPTp coverage. Four health facilities in three districts with high malaria transmission were selected; with baseline and endline surveys conducted, in which the intervention was carried out by community health workers, who were trained and supervised by nurses. IPTp coverage was monitored, and results show an increase in ANC and IPTp4 in both intervention and control groups with IPTp3 and IPTp4 respectively at 50% and 22% in the control versus 64% and 49% in the intervention group at endline. However, no significant difference between controls and interventions was detected. The study revealed that community health workers (CHW) could be trained to provide C-IPTp and is still being implemented in some districts in Burkina Faso.
Jenipher Mukolwe Angaha (Jhpiego, Kenya) shared results from a study in Nigeria and Kenya on the effect of group antenatal care (G-ANC) versus individual ANC on IPTp and ANC attendance. During this study, G-ANC was embraced by both women and health care providers based on many aspects like patient-provider relationship, organisation of care, engagement and empowerment of women. It resulted in increases in ANC attendance and experience of care for women providers and supported further studies on G-ANC to improve coverage of other interventions. The study found the mean number of IPTp doses received was higher for the intervention arm compared to the control arm (Nigeria: 3.45 versus 2.14, p < 0.001; Kenya: 3.81 versus 2.72, p < 0.001).
This report is brought to you by the MESA Correspondents. Senior editorial support has been facilitated by the Organizers and Co-Chairs of the symposia, Valentina Mangano (University of Pisa) and Julie Chaccour (Independent Consultant). This report is cross-posted on the MESA website and on MalariaWorld.