In the early morning of May 5, Beijing time, the top medical journal "New England Medical Journal " (NEJM) published a study online by Gao Fu, director of the Chinese Center for Disease Control and Prevention and academician of the Chinese Academy of Sciences, disclosing the results of the international multicenter randomized, double-blind, placebo-controlled Phase 3 clinical trial of protein subunit new crown vaccine ZF2001.
The ZF2001 vaccine contains SARS-CoV-2 receptor-binding domain (RBD) dimer and aluminum hydroxide adjuvant, which was jointly developed by Gao Fu's team and Anhui Zhifeilong Kema Biopharmaceutical Co., Ltd. Previous Phase 1 and Phase 2 clinical trials have demonstrated that adult vaccination of the vaccine is safe, has acceptable side effects, and is immunogenic.
The clinical trial ended in December 2021. The paper mentions that the Phase 3 clinical trial was conducted in the context of a new wave of SARS-CoV-2 variants dominating the global outbreak. Alpha became popular in early 2021, but was quickly replaced by delta variants over the next few months.
In the Phase 3 clinical trial, the research team chose a three-dose vaccination regimen. The trial was conducted at 31 clinical centers in Uzbekistan, Indonesia, Pakistan and Ecuador; in addition, one clinical center in China was included in the safety analysis only. Adult participants (ages ≥18) were randomly assigned 3 doses of the ZF2001 vaccine or placebo in 25 μg doses (30 days apart) in a 1:1 ratio.
The primary endpoint was the development of symptomatic Covid-19 confirmed by PCR at least 7 days after the third dose. A key secondary efficacy endpoint is the onset of severe to critically ill Covid-19 (including Covid-19-related deaths) at least 7 days after the third dose.
From December 12, 2020 to December 15, 2021, a total of 28,873 participants received at least 1 dose of ZF2001 or placebo and were included in the safety analysis; 25,193 participants who completed the three-dose program were included in the latest major efficacy analysis conducted at the second data deadline of December 15, 2021, which had approximately 6 months of follow-up data.
Of all participants, 27,065 (93.6%) were 18-59 years old, 1,839 (6.4%) aged 60 years and older, and 9,383 (32.5%) were women. 78.5% of the participants were Asian and 17.7% were multiracial. More than 99.9 percent of the participants had not previously been infected with SARS-CoV-2 or had been vaccinated. At baseline, 13.2 percent of the participants had other conditions at the same time.
Short-term follow-up protection showed that at the first data deadline, 663 cases were confirmed with the first dose of vaccination; 224 of these cases became ill at least 7 days after the third dose and were analyzed as the primary endpoint cases. Of these 224 cases, a total of 36 occurred among the 7359 participants in the ZF2001 group and 188 in the 7322 participants in the placebo group. The results of the analysis showed that the protective efficacy of the vaccine was 81.4% (95% confidence interval CI, 73.3-87.3).
In the improved set of complete efficacy analyses, a total of 14 patients met the Covid-19 criteria for severe to critical illness. There was 1 case in ZF2001 group and 13 cases in placebo group. The vaccine was 92.9% effective (95% CI, 52.4- 99.8). A total of 5 Covid-19-related deaths occurred, all in the placebo group. In participants with disease with severe Covid-19 risk factors, the vaccine was 84.4% effective (95% CI, 41.8 to 97.2). The vaccine efficacy was 81.2% (95% CI, 72.8-87.3) among participants aged 18-59 years, and 87.6% (95% CI, 2.5-99.7) in participants aged 60 years and older.
Long-term follow-up protection showed that 1255 cases of Covid-19 were confirmed after the first dose of vaccination at the second data deadline. Of these confirmed cases, 738 developed at least 7 days after the third dose and were assessed as primary endpoint cases. Among them, a total of 158 cases occurred in 12625 participants in the ZF2001 group and 580 cases in 12568 participants in the placebo group. The results of the analysis showed that the protective efficacy of the vaccine was 75.7% (95% CI, 71.0-79.8).
The vaccine was 87.6% effective against severe to critically ill Covid-19 (95% CI, 70.6-95.7), with 6 participants in the ZF2001 group having covid-19 confirmed cases and 43 participants in the placebo group having confirmed Covid-19. The vaccine was effective in 86.5% (95% CI, 38.9-98.5) in Covid-19-related deaths, with 2 participants in the ZF2001 group and 12 participants in the placebo group dying. In participants with disease with severe Covid-19 risk factors, the vaccine was 61.6% effective (95% CI, 29.5-79.9). The efficacy of the vaccine was 76.0% (95% CI, 71.2-80.1) in younger participants (18-59 years), while in older participants (≥60 years), the vaccine efficacy was 67.6% (95% confidence interval 21.9-87.8).
Analysis of the protective power of the ZF2001 vaccine against Covid-19.
In terms of safety, ≥-3 adverse events in the ZF2001 group were rare in both Phase 2 and Phase 3 trials (2.7% vs.1.5%), and serious adverse events clearly associated with ZF2001 were rare (no vs. 2). The incidence of adverse events and reactive events was lower in older participants (≥60 years) than in younger participants (18 to 59 years). The research team believes that these results show that protein subunit vaccines using aluminum adjuvants have good safety.
Adverse event for the second data cut-off date (December 15, 2021).
It is worth noting that, given that the clinical trial was conducted under the leadership of the new crown variant, the research team also analyzed the protective efficacy of the vaccine against different variants. Their results showed that ZF2001 was 92.7% effective against alpha strains in short-term follow-up and 88.3% in long-term follow-up, 81.4% for Delta strains and 76.1% for long-term follow-up, and 84.8% and 75.2% for Kappa (B.1.617.1).
The research team concluded that in a large adult cohort, the ZF2001 vaccine was safe for at least 6 months after full vaccination with the ZF2001 vaccine and was effective in preventing symptomatic and severe to critically ill Covid-19.
In fact, the vaccine was approved for emergency use by China and Uzbekistan in March 2021, the first COVID-19 recombinant protein vaccine approved in the world, followed by emergency use in Indonesia and Colombia, in addition, ZF2001 was approved for conditional marketing in China this year and as a sequential booster for COVID-19 inactivated vaccines.
The technical route of recombinant protein vaccine is also one of the five new crown vaccine research and development technologies deployed in China. The research team believes that the recombinant subunit protein vaccine has the advantages of high yield, high safety, easy storage and transportation, and is one of the important choices for preventing new crown pneumonia.
In an editorial in the New England Journal of Medicine, Dr. Hanna Nohynek, Head of the COVID-19 Vaccine Working Group of the World Health Organization's Strategic Advisory Group, and Dr Annelies Wilder-Smith, Coordinator, noted that despite the global shortage of Covid-19 vaccines in 2021, vaccine availability will no longer be a factor limiting fair vaccination by mid-2022. As of 19 April 2022, approximately 11.5 billion doses of Covid-19 vaccine have been administered worldwide.
However, why do we need a new Covid-19 vaccine? Nohynek et al. argue that each vaccine product has different characteristics and advantages and disadvantages, and that multiple factors must be considered when guiding policy decisions. Different countries and healthcare facilities, as well as different subpopulations and age groups, may benefit from different vaccine products developed on different platforms. When a country decides to procure and introduce a new Covid-19 vaccine, it evaluates outcomes beyond the efficacy and safety assessed in the phase 3 trial. Other important considerations include whether vaccination programmes are easy to implement, how effective the vaccine is when used in routine programs, whether booster injections and frequencies are required, cost, considerations in terms of cold chain logistics, whether production scale can be scaled up, population acceptance, and local or regional production coverage.
In the article, they believe that the development of two new vaccines, such as ZF2001 by Gao Fu et al., and another plant-based coronavirus-like granular vaccine published at the same time, is "commendable." They mentioned that both vaccines have the advantage of not requiring extreme cold-chain storage conditions, making it easier to administer in primary health-care facilities and low- and middle-income countries, and especially that both vaccines are involved in the Phase 3 trials of both vaccines.
Nohynek et al. also caution that several Covid-19 vaccines that were first introduced during the pandemic may not be the best long-term solution. The next generation of Covid-19 vaccines needs to have broader epitope coverage, longer duration of protection, and easy timely updates to create protection against new variants.
In addition, it is worth noting that for the new crown variant strain, Gao Fu's team and cooperative team are still continuing to develop a new generation of recombinant protein vaccines. Just on April 26, the international top academic journal "Cell" online published the research team's important progress in the field of new crown pneumonia vaccine research, the research team developed a chimeric receptor binding domain (RBD) dimer protein vaccine design method for the new crown epidemic variant, which is two heterologous RBD tandem formation, compared with the homologous RBD dimer, chimeric RBD dimer in animals can stimulate a broader spectrum of antibody response and provide better protection.
Mice and rhesus monkeys immune to the prototype-Beta chimeric RBD dimer protein vaccine designed with this strategy showed protective effects on a variety of variants in attack experiments, and the Delta-Omicron chimer RBD dimer vaccine was designed to effectively protect mice against Delta and Omicron infection and pneumonia.