These six research groups funded by Wellcome are bringing diverse scientific approaches to SARS-CoV-2 variant research, engaging with the public and policymakers, and further building groundwork for future responses to infectious disease outbreaks in low- and middle-income countries.
Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS)
Prof Le Van Tan, Dr Chee Wah Tan, Dr Juthathip Mongkolsapaya, Dr Narisara Chantratita, Dr Raph Hamers, Mr Vu Thanh, Prof David Stuart, Prof Susanna Dunachie
Southeast Asia (SEA) represents a weakness in global COVID-19 pandemic response because many countries do not have the required capacity to conduct advanced analysis to determine the potential threat of SARS-CoV-2 variants. Our aim is to develop and apply a multidisciplinary research platform for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby supporting local policy makers with evidence-based decision. We will deliver our proposal through four Objectives:
Establish a new SEA research platform that supports locally-led investigations evaluating the biology of emerging SARS-CoV-2 variants. Employ state-of-the art structural biology to provide rapid prediction of the ability of new variants to evade host immunity and drugs. Evaluate the impact of circulating variants of concern on antibody and T-cell responses in SEA populations, and the clinical consequences of infection. Create a framework for effective communication and engagement with policy makers and the public concerning new virus variants and their potential to threaten public health.
Our proposal will be delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in SEA (Indonesia, Singapore, Thailand and Vietnam), the UK and the USA. It will strengthen regional scientific capacity that can be rapidly deployed for future outbreak responses.
West Africa, West Indies, West London: Mechanisms driving heterogeneity in immunity to SARS-CoV-2 variants (WWW)
Dr David Bauer, Dr Adam Kucharski, Dr C V F Carrington, Dr Emma Wall, Dr Joshua Anzinger, Dr Peter Quashie, Dr Yaw Bediako, Prof Gordon Awandare
Our proposed WWW Consortium brings together three prospective cohort studies of healthy adults in receipt of COVID-19 vaccination in West Africa, the West Indies, and West London to answer fundamental questions in the immunology of SARS-CoV-2 variants. Given the diverse outcomes of COVID-19 in our respective locations, despite many overlapping characteristics such as shared genetic ancestry and AZD1222 vaccination, we have power to make a significant contribution to understanding the mechanisms underlying the apparent heterogeneity in our cohorts. We have 3 aims:
Harmonise our studies to determine the breadth of immunity to SARS-CoV-2 variants by transferring assay and modelling capacity between sites, while also genotype participants to enable comparison across our mixed-ancestry populations;
Test four hypotheses that may contribute to breadth within and between our cohorts: exposure to prior SARS-CoV-2 variants, to other bat & human coronaviruses, to malaria, and to host immunoreactivity; and
Build models of immune responses to variants that incorporating individual-level data and are applicable in LMIC settings with limited datasets.
Together, our work will provide insights into the factors that drive the complex immunology to SARSCoV-2 variants that can also inform future pandemic response in regions currently underserved by both research and surveillance capacity.
Global Knowledge Exchange to Enable In Country Risk Assessment of SARS CoV-2 Variants (G2P)
Prof Wendy Barclay, Dr James Nyagwange, Dr Varadarajan Sundaramurthy, Prof Annapurna Vyakarnam, Prof Bryan Charleston, Prof Martin Antonio, Prof Massimo Palmarini, Prof Michael Malim
SARS-CoV-2 continues to evolve. Novel variants are driven by high levels of global transmission and viral replication, sustained selection pressures imparted by existing immunity acquired through natural infection and vaccination, and increasing use of antivirals. Building on G2P-UK, established working partnerships between teams in the UK, Africa and India, and an ethos of free knowledge exchange, we outline 4 inter-related aims that will enable and prepare G2P-Global to evaluate the significance of emerging viral variation across 3 continents. We will: 1) Implement standardized methodologies that enable rapid in-country risk assessment of the biological and antigenic properties of SARS-CoV-2 variants of concern (VOCs), providing real-time data for guiding infection control and vaccination policies; 2) Undertake discovery-led molecular, cellular and in vivo (hamster) analyses of variant phenotypes to address the mechanistic basis for how the virus can evolve while balancing immune escape with the maintenance of efficient respiratory transmission; 3) Assess the potential for spill-overs into domesticated and wild animal species and subsequent reservoir seeding; 4) Establish communications networks and laboratory resources that will build technical and logistical preparedness enabling G2P-Global partners and additional collaborators to undertake in-country virological assessments of future respiratory virus outbreaks, and associated virus variants.
Can cross-protective airway-resident immunity be harnessed for SARS-CoV-2 variant protection in UK and Malawian populations with or without HIV infection?
Dr Kondwani Jambo, Dr Elena Mitsi, Dr Mariana Diniz, Dr Rhona Mijumbi-Deve, Prof Daniela Ferreira, Prof Henry Mwandumba, Prof Mala Maini
Coinciding with > 70% seroprevalence in Malawi and > 75% vaccination coverage in the UK, the omicron variant has had lower mortality than the delta variant. Both prior infection and vaccination protect against severe COVID-19, and vaccination combined with infection induces highly cross-reactive hybrid immunity. Pre-existing cross-reactive T cells targeting highly conserved replication proteins abort SARS-CoV-2 infection before PCR positivity or antibody seroconversion, leading to protection against COVID-19. Our unpublished data suggest that this rapid immune-surveillance is attributable to pre-existing cross-reactive SARS-CoV-2 T cells that are highly enriched in the human airways. Furthermore, lung-resident B cells elicit antibodies that cross-neutralise influenza variants and recent work has highlighted the protective potential of mucosal IgA against COVID-19. These data suggest that cross-reactive airway immune responses could be critical in defence against emerging variants. We hypothesise that airwaycompartmentalised T and B cells provide an enriched long-lived reservoir of cross-reactive immunity against emerging variants than can protect against COVID-19, and we postulate that is impacted by background exposure, vaccination status and pre-existing HIV infection, in Malawi and UK adults. An understanding of tissue-resident long-lived, broadly cross-reactive immunity is vital for development of next generation mucosal-targeted vaccines and for future studies predicting susceptibility to novel variants.
Platform for rapid immunological characterization of SARS CoV-2 variants in Kenya and the Eastern Africa Region
Prof Isabella Oyier, Dr Charles Sande, Dr Eunice Nduati, Dr George Githinji, Dr James Nyagwange, Dr Peter Borus, Prof Ambrose Agweyu, Prof Philip Bejon
We propose to augment our well-established genomics surveillance infrastructure with a well-structured and coordinated platform for continuous immunological surveillance and characterization of emerging SARS-CoV-2 variants within Kenya and the Eastern Africa region. We will assemble a network of collaborating health facilities across Kenya and the Eastern Africa region to contribute genomic and immunology samples. Our current status as an Africa CDC/WHO-AFRO regional genomic reference laboratory has facilitated bidirectional sample and data sharing with Ministry of Health teams from Eastern Africa and will be a key feature of the immunology work. We will determine whether newly emergent variants exhibit substantial changes in their sensitivity to neutralization by antibodies induced by vaccination and natural infection, and consequently predict the likely impact on vaccine effectiveness. In addition, we will establish a monoclonal antibody discovery pipeline to rapidly identify variant specific or cross-neutralizing monoclonal antibodies. The network will therefore produce directly actionable health intelligence to support local and international public health policy adjustments to curtail the negative health and economic impacts of the virus.
Adaptive responses to SARS-CoV-2 variants in the context of hybrid immunity and immune impairment
Dr Alexander Sigal, Dr Alasdair Leslie, Dr Catherine Riou, Dr Constantinos Kurt Wibmer, Dr Zaza Ndhlovu, Prof Penelope Moore, Prof Wendy Burgers
SARS-CoV-2 evolved variants that could escape previous immunity and transmit better. This process so far culminated in the Omicron variant, which led to a global infection wave of unprecedented scale. To ensure an effective response to variants, their biology, evolution, and mechanisms of escape must be better understood. It is critical to rapidly determine cross-protection afforded by vaccination or previous infections against emerging variants and understand the mechanisms for that protection or lack thereof. This will require understanding B and T cell targets, as well as how these relate to emerging variation, to quickly model/predict new viral escape mutations. Such a high-resolution response is only possible by combining immunology, virology, T and B cell biology, antibody mapping, and structural biology, and will need to be done for increasingly hybrid-induced immunity. The effort must also benefit young investigators.
Specific Aims
1. Perform immunological surveillance of current and emerging variants and predict future mutations which impact antibody and T cell immunity
2. Determine how increasingly complex hybrid immunity functions against current and emerging variants
3. Determine how immune impairment mediated by co-infection with HIV modulates response to variants
4. Promote the next generation of African scientists through cutting-edge research and scientific exchange
