GLOBVAC-Global helse- og vaksin.forskn

Almost 2 million people are infected with HIV annually and up to 30% are young women and teenage girls in sub-Saharan Africa. In addition, India is one of the countries with the largest ongoing HIV epidemic. Until a vaccine is developed, no single product will be able to prevent new HIV infections. Therefore, an "HIV prevention toolbox" has been developed. We want to expand this with broadly neutralizing antibodies (bnAbs) for use as prophylaxis. The aim is to develop an effective preventative product to reduce the incidence of HIV in all low-to-middle income countries. We will further develop bnAbs by adopting our own technologies to improve the duration of action. The aim is to be able to give bnAbs subcutaneously in injection form, which increases the likelihood of effective prophylaxis. Such a strategy will be cost-effective. The project is a collaboration with IAVI in the USA and THSTI in India. THSTI has been on training at IAVI for capacity building, where thorough training has been given in antibody technology, ranging from production to isolation and characterization of bnAbs. Since the start of the project, we have identified Indian donors with the ability to neutralize viruses. The genes from isolated HIV-specific "memory" B cells have been isolated, and a panel of antibodies has been produced where, after characterization, 6 bnAbs were identified. However, the isolated HIV Abs have narrow neutralizing activity. In parallel with this work, IAVI has shared the sequences of a panel of bnAbs with UiO, and UiO has carried out extensive design and production of the variants in combination with Fc design strategies in order to improve the duration of action in the body. These bnAbs have been characterized in a number of systems for binding to HIV antigen and all relevant effector molecules including kinetic measurements. Furthermore, studies have been carried out in humanized mice to derive in vivo pharmacokinetic properties. The results show that the designer variants have a longer duration of action than the antibodies that were the starting point for design. Panels of produced bnAbs were then sent to IAVI where they were tested for their ability to block HIV in neutralization assays, where the results showed that this was the case. These studies led us to the identification of main candidates. This milestone was very important and strongly motivated us to scale up production with the aim of high-quality products ready for studies in non-human monkeys. Next, we scaled up production followed by systematic studies to re-verify the integrity and binding properties of all three partners. Procedures were then established regarding logistics to conduct studies in non-human monkeys where the amounts of antibodies to be given followed by collection of samples combined with methods for quantification. A panel of proteins was sent to our partner in India, where the first set of studies in non-human monkeys was conducted. However, there have been challenges related to subsequent planned studies in non-human monkeys in India, and time has therefore been spent on finding an optimal solution where remaining trials with precious material can be carried out in the USA in collaboration with our partners. A request for revision has been submitted with the need to change the timeline. Despite very difficult working conditions during the pandemic, we have managed to keep the progression on the vast majority of experiments, but there has been a need for necessary changes along the way, which have been made clear in the previously revised plan (approved). A new revision has now been submitted which explains the strategy for reaching the goal with the final attempts. During the course of the project, it has been challenging with COVID-19 in India, which at times has made it difficult logistically. In consultation with the Government of India, THSTI began screening COVID-19 convalescent donors for neutralizing activity using the platform established for HIV, as part of this project. B cells were then sorted and sequenced from these donors. This has led to the isolation of potent neutralizing antibodies that target non-competing epitopes on the SARS-CoV-2 RBD. These antibodies were further evaluated for neutralizing activity against circulating SARS-CoV-2 variants and for protective efficacy against the Wuhan virus in a virus challenge model in transgenic mice at THSTI. The sequences were shared with UiO, and then combined with antibody technologies followed by production and characterization at UiO and with partners. In this case, we also showed that the technologies provided a significantly longer duration of action in humanized mice. In the meantime, omicron emerged and the additional derived variants. The isolated antibodies still have activity against these but reduced. Hence, the specificities should be optimized if a commercialization process is to be considered. In any case, the course of development has shown that

The availability of safe, effective, and affordable HIV prevention products tailored for use by adolescent girls and young women is limited. Indeed, up to 450,000 new infections occur each year among women aged 15 to 24 in sub-Saharan Africa (UNAIDS, HIV prevention among adolescent girls and young women, 2016). Until a vaccine is discovered, a single product or approach will not completely halt new infections and so various prevention products have been developed in the "HIV prevention toolbox." We are proposing to add another component to this toolbox: the use of broadly neutralizing antibodies (bnAbs) for prophylaxis. Using innovative technologies and approaches, we will engineer bnAbs to be safe, affordable, and acceptable to improve uptake by young women and adolescent girls. These efforts will be done in collaboration with leading HIV investigators at the International AIDS Vaccine Initiative (IAVI) in the US and with the Translational Health Science and Technology Institute (THSTI) in India. The impact of this work is to reduce HIV incidence among adolescent girls and young women in sub-Saharan Africa. Now delivering this work within the context of the global pandemic, it is important to note that institutional restrictions in place during periods of lockdown in India dictated that laboratory work was permitted only on SARS-CoV-2. To ensure continuation on the path of strengthening international partnerships and building capacity in India (secondary aims of this study), discovery activities at THSTI have persisted with a revised focus on SARS-CoV-2, demonstrating the team's ability to isolate potent neutralizing antibodies from memory B cells.