Clinical and Regulatory Challenges and Opportunities for Monoclonal Antibodies in Low- and Middle-Income Countries: Lessons from COVID-19 and Beyond.

Monoclonal antibodies are an effective and growing class of pharmaceuticals for the treatment and prevention of a broad range of non-communicable and infectious diseases; however, most low- and middle-income countries have limited access to these innovative products. Many factors contribute to the global inequity of access to these products; however, in this report, we focus on clinical and regulatory complexities as further highlighted by the coronavirus disease 2019 pandemic. Despite a higher prevalence of many diseases in low- and middle-income countries, only 12% of clinical trials for monoclonal antibodies are conducted in these countries. Additionally, only a fraction of the available monoclonal antibodies in the USA and European Union are authorized for use in low- and middle-income countries. Through learnings from desk research and global symposia with international partners, we present recommendations to harmonize processes and facilitate regional and international collaborations for more rapid approval of fit-for-purpose innovative monoclonal antibodies and biosimilars in low- and middle-income countries.

Region-specific laboratory reference intervals are important: A systematic review of the data from Africa.

Region-specific laboratory reference intervals (RIs) are important for clinical trials and these data are often sparse in priority areas for research, including Africa. We reviewed data on RIs from Africa to identify gaps in the literature with a systematic review of PubMed for RI studies from Africa published ≥2010. Search focus included clinical analytic chemistry, hematology, immunological parameters and RIs. Data from adults, adolescents, children, pregnant women, and the elderly were included. We excluded manuscripts reporting data from persons with conditions that might preclude clinical trial participation in studies enrolling healthy volunteers. Of 179 identified manuscripts, 80 were included in this review, covering 20 countries with the largest number of studies in Ethiopia (n = 23, 29%). Most studies considered healthy, nonpregnant adults (n = 55, 69%). Nine (11%) studies included pregnant women, 13 (16%) included adolescents and 22 (28%) included children. Recruitment, screening, enrollment procedures and definition of age strata varied across studies. The most common type of RIs reported were hematology (66, 83%); 14 studies (18%) included flow cytometry and/or T cell counts. Other common tests or panels included liver function assays (32, 40%), renal function assays (30, 38%), lipid chemistries (17, 21%) and serum electrolytes (17, 21%). The number of parameters characterized ranged from only one (three studies characterized either CD4+ counts, D-dimer, or hemoglobin), to as many as 40. Statistical methods for calculating RIs varied. 56 (70%) studies compared their results to international RI databases. Though most presented their data side-by-side with international data with little accompanying analysis, nearly all reported deviation from comparator RI data, sometimes with half or more of otherwise healthy participants having an "out of range" result. We found there is limited local RI data available in sub-Saharan Africa. Studies to fill this gap are warranted, including efforts to standardize statistical methods to derive RIs, methods to compare with other RIs, and improve representative participant selection.

Status of vaccine research and development of vaccines for HIV-1.

Human immunodeficiency virus (HIV) is the cause of one of the most lethal pandemics in human history, although in recent years access to highly effective anti-retroviral therapy has provided new hope worldwide. Transmission of HIV by sexual contact, childbirth and injection drug use has been reduced, but 2 million are newly infected each year, and much of the transmission is from people who do not know their status. In addition to known methods, a preventive vaccine is needed to end the pandemic. The extraordinary mutability and genetic diversity of HIV is an enormous challenge, but vaccines are being designed for broad coverage. Computer-aided design of mosaic immunogens, incorporating many epitopes from the entire genome or from conserved regions aim to induce CD8+ T cells to kill virus-infected cells or inhibit virus replication, while trimeric envelope proteins or synthetic mimics aim to induce broadly reactive neutralizing antibodies similar to those cloned from some infected patients. Induction of more potent and durable responses may require new adjuvants or replicating chimeric vectors chimeras that bear HIV genes. Passive or genetic delivery of broadly neutralizing antibodies may provide broad protection and/or lead to insights for vaccine designers. Proof-of-concept trials in non-human primates and in one human efficacy trial have provided scientific clues for a vaccine that could provide broad and durable protection against HIV. The use of vaccines to destroy HIV reservoirs as part of therapy or cure is now also being explored.