COVID-19 vaccines: breaking record times to first-in-human trials

The twenty-first century has come with a new era in vaccinology, in which recombinant genetic technology has contributed to setting an unprecedented fast pace in vaccine development, clearly demonstrated during the recent COVID-19 pandemic.

novel COVID-19 vaccine based on an adenovirus vector 5 (Ad5-nCoV) encoding the full-length S protein has progressed fastest and has now entered phase II trials from 12th April 2020. The INO-4800, DNA plasmid-based vaccine encodes the S protein and is delivered by two intradermal injections followed by electroporation of the DNA vaccine in healthy volunteers. The COVID-19 specific aAPC vaccine has been prepared by transfection of aAPCs with a genetically-modified lentivirus encoding the SARS-CoV-2 structural and protease protein domains to aAPCs, which are delivered by three subcutaneous injections to healthy and COVID-19 positive volunteers between age of 6 months to 80 years. The lentiviral-based COVID-19 (LV-DC) vaccine and antigen-specific cytotoxic T cell (CTL) vaccine encoding COVID-19 antigens were given via subcutaneous injection and intravenous (IV) infusion respectively to the volunteers including the laboratory (RT-PCR) confirmed COVID-19 infections as part of Phase I/II trial. In addition, a COVID-19 vaccine based on Chimpanzee Adenovirus Vector (ChAdOx1) developed by University of Oxford has entered phase I/II clinical trial in April 2020 to test its safety, tolerability and reactogenicity profile, as well as its immunogenicity in 510 volunteers. This vaccine also aims to be assessed for efficacy to prevent infection measured by PCR as well as symptomatic infection (NCT04324606). Chimpanzee adenoviral vectors are replication-deficient vaccines that carry one or a few encoded antigens and efficiently stimulate both arms of the adaptive immune responses: humoral and cytotoxic T-cells (CTLs). They have been very well-studied as a vaccine platform in over 10 different pathogens with safe profile in thousands of volunteers from 1 week of age to 90 year-old volunteers 7 .
In comparison, other Coronaviruses such as MERS-CoV 8 and SARS-CoV 9 have reached clinical trials within~22 months and 25 months, respectively after their outbreaks (NCT02670187, NCT00099463). Both first clinical trials were based on DNA vaccines encoding the spike (S) glycoprotein and even though the results of the SARS-CoV vaccine have not been published yet, MERS-CoV DNA vaccine preliminary results showed good tolerability and immunogenicity in humans, with immune responses similar to the ones elicited after natural infection, which supports further development.
This pace of development is striking when compared to new emerging diseases causing major epidemics declared by the WHO such as the arboviral diseases Dengue 10 , Chikungunya 11,12 and Zika [13][14][15] , which reached trials in 52,~19 and~9 years after declaration of major outbreaks, respectively ( (13) NCT02840487). Dengue Virus has been in circulation for more than a century and a tetravalent live attenuated vaccine produced by Sanofi Pasteur has only been authorized by the European Medicine Agency in 2018. However, the very first clinical trial was done during the World War II by Albert Sabin, who used a Dengue virus originally attenuated in mice 16 . The first chikungunya vaccine tested in humans in the late 60's used a formalininactivated virus 17 , which was subsequently abandoned for new vaccine platforms such as a virus-like particle particle (VLP) platform (NCT01489358), which has showed high titters of neutralizing antibodies in recipients after a second dose 18 . The first Zika DNA vaccine reached trials in August 2016, 9 years after ZIKV outbreak in part of the Federated States of Micronesia, 3 years after the major epidemic in French Polynesia in October 2013 but just 6 months after WHO declaration as the Public Health Emergency of International Concern (PHEIC) on February 2016, highlighting the advances in the modern vaccine development in urgent need. A Zika DNA vaccine delivered in a split-dose needle freeway, was able to induce six times higher immune responses compared to a single-dose delivery via needle and syringe and therefore moved into an international placebo-controlled phase 2 efficacy trial 19 .
Other emerging diseases that have caused major epidemics are Haemorrhagic fever viral diseases such as Ebola 20 , Crimean-Congo fever 21 and Lassa fever 22 . These have taken more than three decades to get to the first-in-human assessment (NCT00072605, NCT03020771, NCT03805984) ( Fig. 1) but unfortunately not all of them have described safety and tolerability results yet. However, the rVSV-Ebola vaccine candidate based on a live, attenuated recombinant vesicular stomatitis virus vector produced by Merck has progressed beyond I/II/III clinical trials 23,24 receiving approval by the US FDA 25 in December 2019; whereas a viral-vectored Ebola vaccine candidate consisting of Ad26/MVA has now completed phase III trial (NCT02543567). Initial vaccine clinical trials may not always lead to a successful license but can pave the way to the success of future vaccines in acquiring the license.
The great majority of licensed vaccines are based in inactivation/attenuation pathogens which lengthen the development, cost and production of the vaccine. Recombinant viral vectored, DNA/RNA and protein technologies are setting the fastest records in vaccine development but just a selected few have been licensed so far for veterinary use only, since, for humans some vaccines have not met some regulatory requirements for approval and commercialization yet but international emergencies like the current COVID-19 could provide a final push towards obtaining licensure. This highlights the potential of vaccinology to make fast progress when appropriate international support exists, proving that when there is a will, there is a way.