Looking beyond COVID-19 vaccine phase 3 trials

Perspective https://doi.org/10.1038/s41591-021-01230-y Looking beyond COVID-19 vaccine phase 3 trials Jerome H. Kim 1 ✉, Florian Marks1,2,3 and John D. Clemens1,4,5 After the recent announcement of COVID-19 vaccine efficacy in clinical trials by several manufacturers for protection against severe disease, a comprehensive post-efficacy strategy for the next steps to ensure vaccination of the global population is now required. These considerations should include how to manufacture billions of doses of high-quality vaccines, support for vaccine purchase, coordination of supply, the equitable distribution of vaccines and the logistics of global vaccine delivery, all of which are a prelude to a massive vaccination campaign targeting people of all ages. Furthermore, additional scientific questions about the vaccines remain that should be answered to improve vaccine efficacy, including questions regarding the optimization of vaccination regimens, booster doses, the correlates of protection, vaccine effectiveness, safety and enhanced surveillance. The timely and coordinated execution of these post-efficacy tasks will bring the pandemic to an effective, and efficient, close. T he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a powerful reminder of the ability of infectious diseases to sicken, kill and disrupt, even in the most technologically advanced societies The rapid announcement of the outbreak and early publication of the viral sequence enabled work on a vaccine solution to proceed within weeks of China’s initial notification of the World Health Organization (WHO) on 31 December 2019, of the outbreak1. Funding of grants for vaccine development from the Coalition for Epidemic Preparedness Innovations (CEPI) was announced in January 2020 (ref. 2). Additional monies for vaccine development were also provided by national and multilateral research funders, with Operation Warp Speed (OWS) in the United States being the largest at $18 billion3 (Fig. 1). Achieving the goal of development of a safe and efficacious vaccine had a 6- to 18-month timeline. The unprecedented effort has generated over 200 candidates in various stages of development, with over 50 candidate vaccines in human clinical trials and 18 in efficacy testing4. To date, Pfizer/BioNTech has announced efficacy of 95%5; Gamaleya has announced efficacy of 92%; Moderna has announced efficacy of 94.5%; and AstraZeneca has announced efficacy of 70%5,6. Sinopharm has now announced efficacy of 79%, and several countries participating in the Sinovac (another Chinese company) efficacy trials have announced efficacies (for the same product) of 50%, 65%, 78% and 91%7,8. Sinovac has yet to comment, and these data have not been published or peer reviewed. Pfizer/ BioNTech and Moderna are RNA vaccines expressing the coronavirus disease 2019 (COVID-19) spike glycoprotein, whereas vaccines from Gamaleya and AstraZeneca (partnered with Oxford University) express spike protein from adenovirus vector platforms. The vaccine developed by Gamaleya has a heterologous approach, with spike delivered in an adenovirus type 26 vector first, followed by a second dose containing spike in an adenovirus type 5, and AstraZeneca uses a chimpanzee adenovirus-expressing spike. Sinopharm and Sinovac have whole inactivated virus vaccines with alum as an adjuvant. However, effective vaccination is one part of effective, comprehensive control of the pandemic. In addition, scientific, social and political questions—around dose, schedule, ethics, effectiveness, surveillance and vaccine hesitancy—remain to be resolved, and pandemic control will require that some, if not all, of these issues be solved intercurrently. Vaccine manufacturing Once shown to be safe and efficacious, a vaccine must be manufactured to the current good manufacturing practices (CGMP) international standard9,10. Current estimates of the level of effective population immunity for interruption of transmission is ~60–70%, but vaccination coverage required by a partially effective vaccine to interrupt transmission might be higher. With 8 billion people to vaccinate with a two-dose regimen, we might need 10–11 billion doses to interrupt transmission. CEPI estimates global vaccine manufacturing capacity at 2–4 billion doses annually, and that it will be 2023–2024 before enough vaccine can be manufactured.11 This capacity might be product specific, and there might be some limitations: whole-inactivated vaccines, for instance, must be manufactured in biosafety level 3-capable facilities. In addition to the administrative process of licensing and the subsequent technology transfer, the scale-up of vaccine manufacturing might be associated with unforeseen problems in the vector, purification or formulation. Several of the companies with products in efficacy testing (phase 2/3 or phase 3) have announced that they have started increasing production in anticipation of proof of efficacy and safety. Companies have sought partners for manufacturing to scale-up to the level of hundreds of millions of doses. AstraZeneca has partnered with Serum Institute of India and SK Bioscience (Republic of Korea) for its chimpanzee adenovirus-vectored SARS-CoV-2 vaccine. Sinovac (China) has partnered with Butantan (Brazil) and Bio Farma (Indonesia). Johnson & Johnson has engaged Biological E (India). OWS has $1.6 billion in arrangements with ‘non-vaccine’ manufacturers that include different contract manufacturers, including, for instance, the manufacture of medical glass for vaccine vials3. Quality. Vaccine quality is often taken for granted, but both safety and efficacy can be affected by even minor lapses in quality. Country-specific regulatory requirements and a set of international standards developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH, https://www.ich.org/) provide the basis for ensuring quality in clinical research, while ICH Q series guidance ensures that vaccine quality meets global standards for chemistry, manufacturing and control. In addition, research laboratories supporting vaccine development must ensure alignment with Good 1 International Vaccine Institute, Seoul, Republic of Korea. 2Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge School of Clinical Medicine, Cambridge, UK. 3University of Antananarivo, Antananarivo, Madagascar. 4International Centre for Diarrheal Diseases Research, Dhaka, Dhaka, Bangladesh. 5UCLA Fielding School of Public Health, Los Angeles, CA, USA. ✉e-mail: Nature Medicine | VOL 27 | February 2021 | 205–211 | www.nature.com/naturemedicine 205 Perspective NATure MeDICIne Future directions Approval y c ica f Ef Global vaccination Manufacturing • Quality • 2–4 billion doses/year • WHO PQ • Logistics: factory to the ‘last mile’ • Cold chain • Prioritization • Other preventive measures • Delivery • Pivot to universal (...truncated)