“Let’s say these vaccines were out and they were available to you and somebody said to you ‘How would you like to participate in a trial where you have … 50 percent chance of not getting a vaccine.’ How enthusiastic would you be?”
-- Dr. Gordon Guyatt
Recently, there has been emerging good news regarding the development and testing of vaccine candidates against COVID-19. On November 9 and 16, 2020, Pfizer (along with BioNTech) and Moderna both released positive and promising preliminary results from their phase III clinical trials testing the efficacy of COVID-19 vaccine candidates. On November 18, the CEO of Pfizer announced their final analysis, which showed that their vaccine candidate had a very high efficacy in protection against SARS-CoV-2 infection without major safety concerns. This exciting news, as the Prime Minister of Canada Justin Trudeau commented, made people see “the light at the end of the tunnel” (Source).
But how should we interpret the vaccine efficacy rates? How optimistic should we feel about the efficacy of the vaccines? How much longer do we have to wait to get vaccinated and have the pandemic finally under control? And will the introduction of the leading vaccines to the marketplace stall further vaccine development? There are still many questions that need to be answered. In this OE Original, we aim to provide insight into these questions by introducing the 2 new vaccine candidates developed by Pfizer and Moderna.
The names of the vaccine candidates developed by Pfizer and Moderna are BNT162b2 and mRNA-1273, respectively. Both of them belong to the family of mRNA vaccines, a type of the nucleic acid-based vaccine.
Both vaccines encode a prefusion stabilized membrane-anchored SARS-CoV-2 spike glycoprotein, which plays a critical role in viral entry through mediating host cell attachment (Belouzard et al., 2012; Jackson et al., 2020; Walsh et al., 2020). In addition to mRNA vaccines, other types of vaccine candidates against COVID-19, such as DNA vaccines (Smith et al., 2020) and recombinant viral-vectored vaccines (Zhu et al., 2020), have also chosen the SARS-CoV-2 spike glycoprotein as a target for vaccine development.
The major advantages of mRNA vaccines are that they are synthesized by in vitro transcription and do not involve any microbial molecules (Pardi et al., 2018). Therefore, these vaccines are non-infectious to the vaccine recipients and potentially safer than other types of vaccines which contain viral components, such as live attenuated and inactivated viral vaccines (Jeyanathan, et al. 2020).
The Results of the mRNA Vaccine Trials
Both companies reported the efficacy rates of their vaccine candidates using percentage. Firstly, let’s look at how the efficacy rate was calculated here. In the two phase III clinical trials, participants who had no prior SARS-CoV-2 infection were randomly assigned to the vaccine group or placebo group. With both vaccines, each participant received two injections. Afterwards, participants were followed up, and the cases of newly developed SARS-CoV-2 infection in each group were recorded. The formula to calculate the vaccine efficacy rate is as follows:
Vaccine efficacy rate (%) = (COVID 19 cases in placebo group - COVID 19 cases in vaccine group) ÷ COVID 19 cases in placebo group × 100
The Phase III clinical trial of BNT162b2 developed by Pfizer has enrolled about 43538 participants as of November 9, 2020 (Source). The enrolment will continue until a total of 164 confirmed COVID-19 cases have accrued. The interim analysis, which was conducted on November 8, involved 94 confirmed cases of COVID-19. The interim analysis found that there is an over 90% protection rate in preventing COVID-19 in vaccinated participants without evidence of prior SARS-CoV-2 infection at 7 days after the second dose of vaccine, compared to those who received placebo. Using absolute numbers, over 90% protection rate means that among 94 participants who contracted COVID-19, no greater than 8 of them received the vaccine candidate -- BNT162b2, while more than 86 participants received placebo. Additionally, the preliminary results have not reported any serious safety concerns.
On the morning of November 18, Pfizer announced their final results for BNT162b2 (Source). It showed that among the 170 confirmed cases of COVID-19, 8 cases received the vaccine whereas 162 of them received placebo. The protection rate of BNT162b2 reached about 95% (P < 0.0001) in participants without prior SARS-CoV-2 infection from 7 days after the second dose of vaccine. The protection was consistent across some demographic characteristics, such as age. The vaccine efficacy rate among volunteers at the age of over 65 years old was greater than 94%. Ten severe COVID-19 cases were observed in the trial, with 9 of them occurring in the placebo group and 1 in the vaccinated group, indicating that Pfizer’s vaccine might not only block the infection from the SARS-CoV-2 virus, but also protect people who get infected from developing a severe condition. Pfizer also revealed more details about safety outcomes in their release. BNT162b2 was well tolerated, with the adverse events (= 2% in frequency after the first or second dose of vaccine) being fatigue (3.8%) and headache (2.0%) following the second dose.
The phase III clinical trials conducted by Moderna recruited more than 30000 volunteers from 100 clinical research sites in the United States. In their interim analysis, Moderna, on November 16, claimed that the protection rate of their vaccine candidate -- mRNA-1273 was about 94.5% based on 95 participants who got infected with SARS-CoV-2 during follow-up (Source). This means that 90 of the participants, who were confirmed cases of COVID-19 during follow-up, had received the placebo, and only 5 had been given the vaccine. The findings were statistically significant, meaning they are likely not due to chance. There were 11 severe COVID-19 cases out of the 95 confirmed cases, all of which occurred in the placebo group. The vaccine was well tolerated among participants.
Both companies have only released the point estimates of vaccine efficacy rate; neither of them reported the 95% confidence intervals of efficacy rates.
How Valid are the Results?
The minimum requirement of approving a COVID-19 vaccine set by the World Health Organization (WHO) is a point estimate of at minimum 50% protection rate in the general population in preventing COVID-19 of any severity or just severe cases, or preventing shedding or transmission of COVID-19 (WHO, 2020). However, preferably, the WHO will require a vaccine candidate to show at least a 70% of efficacy rate across the general population.
The point estimate of the vaccine efficacy rate which the United States Food and Drug Administration (US FDA) would use to approve a vaccine against COVID-19 is also at least 50% (FDA, 2020). This efficacy should be achieved ideally in the context of preventing any severity of COVID-19 infection, including mild and severe cases. However, the FDA will also consider approval if the vaccine can reach the 50% efficacy rate only in the prevention of severe COVID-19.
Both the point estimates of the vaccine efficacy rate reported by Pfizer (95%) and Moderna (94.5%) are far beyond the standard required by the WHO and FDA. However, neither company reported the 95% confidence interval (95% CI) for their point estimates. The FDA requires the lower bound of the CI around the point estimate to be greater than 30% (FDA, 2020). Therefore, from the point of view of the point estimates of the vaccine efficacy rate, the 2 vaccine candidates were satisfying; however, more details, specifically on 95% CIs, are needed for further evaluation regarding precision of their results.
Also, it is too early to know how long the protection from the 2 vaccine candidates will last or their long-term safety outcomes. The WHO prefers that the vaccine is able to confer protection for at least one year, but will also accept a protection period no shorter than 6 months (WHO, 2020). The FDA (2020) requires a period of follow-up between 1 and 2 years. Pfizer intends to continue following up with the volunteers for long-term protection and safety for 2 years after their second dose of vaccines.
Finally, the outcome reported by Pfizer and Moderna was the incidence of symptomatic COVID-19 among participants without prior infection of SARS-CoV-2. Neither of them provided information on whether or to what extent the 2 vaccine candidates could protect participants from contracting asymptomatic COVID-19. This is also an important information needed to follow up because controlling asymptomatic COVID-19 cases, in addition to monitoring symptomatic cases, is a crucial mitigation strategy to limit the spread of COVID-19.
What are the Next Steps for the 2 Vaccine Candidates?
Pfizer has submitted the application for emergency use authorization (EUA) to the FDA within days and plans to share their data with other regulatory agencies all over the world. Moderna has only released the preliminary results, so further actions will depend on the final results.
After approval, Pfizer expects to produce up to 50 million vaccine doses by the end of 2020 and up to 1.3 billion doses by the end of 2021 (Source). Moderna, on the other hand, is capable of manufacturing 400 million doses annually and aims to produce 500 million to 1 billion doses in 2021 (Source).
What are Potential Challenges Before we can get the Vaccines?
As mentioned previously, these 2 mRNA vaccines are considered safe in patients because they do not contain any viral components. Moreover, mRNA vaccines are relatively quick to manufacture.
Despite the advantages, there are some potential challenges for the general public getting vaccinated with the 2 vaccine candidates. One challenge is that mRNA vaccines are a relatively new type of vaccine platform. No mRNA vaccine has yet been licensed for wide human use (Jeyanathan, et al. 2020). If BNT162b2 and mRNA-1273 are approved in the near future for preventing COVID-19, they will be the first of its type. Therefore, we may encounter some unknowns in the future.
Another major challenge is that mRNA is not very stable by nature and needs to be transported and stored under ultra-low temperature in order to keep its quality. The WHO requires that vaccines for COVID-19 should have a shelf life (the length of time that a vaccine may be stored before becoming unfit for use) of at least 12 months in the condition of -60°C to -70°C, and at least 2 weeks at 2°C to 8°C during the outbreak period (WHO, 2020). For the long term, it is necessary for the vaccine to be stored at -20°C or higher (WHO, 2020). Moreover, WHO strongly prefers a higher storage temperature and higher thermostability, which will greatly enhance COVID-19 vaccine stability and distribution (WHO, 2020). Pfizer’s vaccine BNT162b2 needs a temperature condition of -70°C ± 10°C to be transported and stored (Source), which can pose an obstacle for hospitals or health care facilities, especially those in underdeveloped regions. Moderna’s vaccine may be more advantageous in terms of the temperature requirements: mRNA-1273 could remain stable for 6 months under -20°C and for 30 days at a temperature of 2°C to 8°C (Source).
Will the introduction of the leading vaccines to the marketplace stall further vaccine development?
The promising results of the 2 vaccine candidates do not mean we can stop vaccine development and testing. On the contrary, it is still necessary and critical to keep exploring other types of COVID-19 vaccine candidates due to the disadvantages of mRNA vaccines mentioned in the previous section, such as that no mRNA vaccines have been widely used in humans and the difficulties in transportation and storage of mRNA vaccines. Despite the public’s excitement about the 2 vaccine candidates developed by Pfizer and Moderna, medical experts have been expressing their concerns about how approval of the 2 vaccines will impact those still under early investigation or will be investigated.
There will be an ethical issue if future trials try to compare other vaccine candidates with placebo once Pfizer and Moderna’s vaccine candidates receive the approval and become widely accessible. As Dr. Guyatt pointed out, people may not be enthusiastic about participating in a clinical trial in which they have a 50% chance of receiving placebo. Although future trials can compare their vaccine candidates with already approved vaccines instead of a placebo, this will require a much larger sample size and longer follow up to have adequate statistical power, and therefore, very challenging for carrying out a trial.
Just before the publication of this OE Original, AstraZeneca also released their COVID-19 vaccine (AZD1222) preliminary data on November 23, 2020 (Source). Different from those developed by Pfizer and Moderna, AstraZeneca’s vaccine candidate is not an mRNA vaccine but the recombinant viral-vectored vaccine.
Recombinant viral-vectored vaccines are built on either an attenuated replication-competent viral backbone or a replication-deficient viral backbone in order to express antigens of the target pathogen, (Jeyanathan et al., 2020). AZD1222 is built using the backbone of chimpanzee-derived adenovirus. The identifier for the phase III trial sponsored by AstraZeneca is EudraCT 2020-001228-32.
The interim analysis of clinical trials of AZD1222 in the UK and Brazil involved 131 confirmed cases of COVID-19. The average protection rate of AZD1222 was about 70% in participants without prior SARS-CoV-2 infection from 14 days or more after receiving two doses of the vaccine. Seventy percent protection rate means that among 131 participants who contracted COVID-19, about 30 of them received the vaccine candidate, while around 101 participants received placebo. AZD1222 was well tolerated, and no vaccine-related serious safety events have been reported. Like Pfizer and Moderna, AstraZeneca is trying to get approval for their vaccine candidate and aims to produce up to 3 billion doses in 2021.
Although the efficacy of AZD1222 seems not as impressive as those of Pfizer and Moderna’s mRNA vaccines, one of the major advantages of AZD1222 is that the vaccine does not require ultra-low temperature and can be stored, transported, and handled at normal refrigerated conditions (2°C - 8°C) for at least 6 months.
On the one hand, the success of a new type of vaccine candidate which is not an mRNA vaccine offers us more options. However, the ethical issue, in which future trials may not be able to compare other vaccine candidates with placebo, still remains.
To date, close to 1.4 million people have died globally due to COVID-19 (Johns Hopkins COVID-19 map). Promising vaccine testing results provided by Pfizer, Moderna, and AstraZeneca have given everyone hope to have the pandemic under control as soon as possible. However, challenges still remain for massive vaccination in general populations. Ethical issues are also raised by the introduction of the leading vaccines to the marketplace for future trials comparing vaccines with placebo, which may stall further vaccine development.
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Zhu, F.-C., et al. (2020). Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet, 395(10240), 1845-1854. doi:10.1016/S0140-6736(20)31208-3