Global COVID-19 Vaccine Race; Where are we at right now?
Chulwoo Rhee, T. Anh Wartel, Jerome H. Kim
International Vaccine Institute
The SARS-CoV-2 pandemic continues, sustained by chains of transmission and crisscrossing international borders, without an end in sight . It counts hundreds of thousands of deaths, over 15 million infections, immeasurable disruption of lives, and dislocation of society and economies on a global scale [2-3]. Elderly populations with pre-existing comorbidities, people with low socio-economic status and sub-optimal access to medical care are the most vulnerable to this deadly virus [4-5]. To put an end to this pandemic, a safe and effective vaccine against SARS-CoV-2 is urgently needed to prevent new infections, establish herd-immunity, and slowly return to pre-COVID-19 normality. As of 20 July 2020, 24 vaccine candidates have entered into clinical evaluation, with 142 candidates at preclinical development stage (Figure 1) . In this article, we would like to summarize preliminary findings of five vaccine candidates that have reported in peer-reviewed journals or have publicly announced interim results.
Figure 1. Number of Vaccine Candidates Reported to World Health Organization by Vaccine Platform
1. CanSino Non-replicating Adenovirus type-5 (Ad5) Vectored Vaccine
The phase I study is a single-center, open-label, non-randomized, dose-escalation trial of an Ad5 vectored COVID-19 vaccine candidate conducted in Wuhan, Hubei Province , the epi-center where reported the first outbreak of COVID-19 in China . The study which enrolled 108 healthy adults between 18-60 years, 36 each in low-(5x1010 viral particles), middle-(1x1011 viral particles), and high-dose (1.5x1011 viral particles) groups, showed that the high dose of the vaccine candidate tended to be more immunogenic than the low- and middle-dose vaccines, and it was also associated with a relatively higher reactogenicity profile in the high dose group . Further clinical development with a randomized, double-blinded, placebo-controlled, phase II study in 603 volunteers aged 18 years or older is underway and the interim results confirmed Ad5-vectored vaccine with low dose (5x1010 viral particles) is safe and induced significant immune responses in the majority of the study participants after a single dose. .
2. University of Oxford/AstraZeneca Non-replicating Chimpanzee Adenovirus-Vectored (ChAdOx1 nCoV-19) Vaccine
The ChAdOx1 nCoV-19 vaccine consists of the non-replicating simian adenovirus vector, containing the spike protein of SARS-CoV-2. The phase I/II, participant-blinded, multi-center, randomized controlled trial aimed to enroll 1,090 subjects to ChAdOx1 nCoV-19 vaccine or meningococcal conjugate vaccine has completed the enrollment and is currently in follow up . The recently published data from 1,077 study participants  showed an acceptable safety profile and demonstrated neutralizing antibody responses against SARS-CoV-2 in 91% (32/35) participants after a single dose measured in a microneutralization assay and 100% (35/35) when measured by 50% plaque reduction neutralization assay. Ten subjects were given a booster dose at 28 days after the first dose, and 100% (10/10) subjects showed neutralizing activity. Spike-specific T-cell responses peaked on day 14. Phase II with expanded age group is ongoing  as well as phase III study .
3. Moderna mRNA Vaccine
mRNA-1273, a lipid nanoparticle–encapsulated, nucleoside-modified messenger RNA (mRNA)–based vaccine, encodes the spike glycoprotein which mediates host cell attachment and viral entry to a cell . The phase I study is a dose-escalation, open-label design, enrolling 45 healthy adults between 18-55 years. The candidate vaccine is given in two injections at doses of 25 μg, 100 μg, or 250 μg 28 days apart . The interim analysis reported that mRNA-1273 was generally well tolerated and has shown robust binding antibody responses to both full-length S-2P and receptor-binding domain as well as dose-response relationship. Binding and neutralizing antibody titers after the two-dose vaccine series have demonstrated immune responses similar to those found in convalescent sera. Enrollment of phase IIa, randomized, observer-blind, placebo-controlled, dose-confirmation study with target size for 600 participants is on-going , and phase III, randomized, stratified, observer-blind, placebo-controlled study for evaluating efficacy in 3,000 adults 18 years or older is currently being planned later this summer .
4. BioNTech/Pfizer 3 LNP-mRNA Vaccine
Four mRNA constructs, nucleoside-modified messenger RNA vaccine candidates expressing the SARS-CoV-2 receptor binding domain (RBD), are being evaluated among 45 subjects in an ongoing placebo-controlled, observer-blinded clinical trial . The study is comprised of three stages. Stage 1 aims at identifying optimal vaccine candidates, dose level, and number of doses. Stage 2 expands vaccinated age groups, and stage 3 is for safety and efficacy. Pfizer and BioNTech jointly announced that one of four candidates, BNT162b1, early data had demonstrated significant induction of RBD-binding IgG antibodies and SARS-CoV-2 neutralizing antibodies . Further data from the ongoing clinical trial will enable selection of a lead candidate and dose level for a large, global phase IIb/III safety and efficacy study that may begin later this summer.
5. Inovio DNA Vaccine with Electroporation
INO-4800, a DNA plasmid vaccine candidate against SARS-CoV-2, is currently being evaluated in clinical trials in US and Republic of Korea [21, 22]. The phase I clinical trial of INO-4800 initially enrolled 40 healthy adults 18 to 50 years of age, 20 participants each with two doses of either 1.0mg or 2.0mg, four weeks apart. Each intradermal injection is followed by electroporation, a procedure intended to effectively deliver plasmid vaccine inside the cell. The biotech company announced the vaccine candidate had elicited both humoral and cellular immune response at week 6 by demonstrating a 94% overall immune response rate , consistent with findings from animal studies .
Aggressive provision of public research funding, public-private partnership strategies, global collaboration and a competitive R&D environment have accelerated vaccine clinical development against SARS-CoV-2, enabling a few candidates to enter efficacy trials within a few months of identification of the virus and publication of its genetic sequence. Vaccine candidates have demonstrated acceptable safety and tolerability profiles as well as promising humoral and cellular immune responses. Late stage of development with phase IIb/III trials will hopefully provide evidence of safety and efficacy in study participants. However, there is a need to also follow the study participants for longer periods (at least 1-2 years after study completion) for rare safety events detection and protection longevity. Last but not the least, it is of paramount importance that any vaccine for COVID-19 to have mechanisms in place  to ensure rapid roll-out, fair distribution, and equitable access to vaccine globally.
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