An illustrative photograph showing a person holding a vial marked ‘COVID-19 vaccine’. Photo: Nataliya Vaitkevich/Pexels.
On Monday, November 9, the US-based drug-maker Pfizer announced that its COVID-19 vaccine candidate, which it is co-developing with the German company BioNTech, is more than 90% effective. On November 16, Moderna, another US-based drug-maker, also announced more than 90% efficacy for its vaccine candidate. These efficacy levels are way beyond the US drug regulator’s 50% threshold. Both these companies plan to seek emergency use authorisations (EUAs) for their COVID-19 vaccine candidates by the end of this month.
What is special about these vaccine candidates? Are they going to help us stop the pandemic?
A virus represents a set of unique genetic instructions, somewhat like computer software. Scientists at BioNTech and Moderna independently designed a piece of genetic software coding for the SARS-CoV-2 spike (S) protein. They inserted this S protein code into a messenger RNA (mRNA) molecule. When this mRNA is injected into the body, cells receiving it make the S protein and display it on their surface. This puts the immune defence system on high alert for the actual virus, which the body may later encounter in a natural infection. This is a neat trick of biology – to get the body to produce its own vaccine.
Both Pfizer and Moderna launched their efficacy trials in the last week of July this year. The trial investigators randomly assigned the participants, in equal numbers, to either a treatment group or a control group. They administered their mRNA vaccine candidate to people in the treatment group and saline (salt water) to those in the control group. They gave two doses, three weeks (Pfizer) or four weeks (Moderna) apart, to all participants.
The trials are still underway and are likely to be completed in last quarter of 2022, by which time, the trial investigators would have injected their vaccine candidates into several thousands of volunteers.
At the time of the interim analysis, 94 of the trial participants in the Pfizer trial, and 95 in the Moderna trial, had reportedly tested positive for SARS-CoV-2 infections. Using this information, both companies reported the efficacy of their vaccine candidates to be more than 90% each. This means that only about 10% of all COVID-19 cases identified at the time of interim analysis belonged to the vaccine groups.
In a non-pandemic situation, a vaccine developer typically completes the phase-3 trial before approaching drug regulatory agencies to obtain a commercial license. The US drug regulator has specified that it may consider granting an EUA before phase 3 trials are completed if the vaccine developer meets two conditions: show at least 50% efficacy, and provide two months of safety data for at least half the number of participants.
Pfizer and Moderna plan to apply for such EUAs by the end of November 2020. Barring any unforeseen delays, public health experts expect the vaccines to receive EUA by early 2021. Still, these will remain unlicensed vaccine candidates.
Together, these two companies are expected to be able to provide 50-60 million doses by the end of this year and two billion or more doses by the end of 2021. Moderna claims an edge as its mRNA vaccine candidate is stable at normal fridge temperatures – while the Pfizer/BioNTech candidate needs ultra-low freezer temperatures.
The US has pre-purchase agreements with both these companies and will have access to adequate number of vaccine doses for its entire population. But whether these two candidates will eliminate the COVID-19 crisis is an open question at this time.
Vaccine efficacy and safety
The efficacy of licensed vaccines range from 40-60% for influenza to more than 95% for measles and polio. Against this, the 90% or higher efficacy reported by Pfizer/BioNTech and Moderna are very good. But two points are relevant here. One, the companies estimated efficacy based on interim analyses of fewer than 100 COVID-19 cases – so the final efficacy is likely to be different when the trials are completed, in about a year from now. Two, these efficacies have been determined under optimised conditions during well-controlled phase 3 trials. The actual efficacy in the less-than-perfectly-controlled real world – also called the effectiveness – can be known only after the vaccines have been given to millions of people.
As for the safety: In a prior phase 1 trial, with a small numbers of volunteers, the Pfizer/BioNTech vaccine candidate caused mild to moderate side effects; some volunteers also reported some serious side effects. Moderna also reported mild or moderate side effects after its phase 1 trial, and serious side effects in three volunteers in a phase 1 trial.
The mRNA vaccine technology is new and needs careful and extensive safety testing. Both Pfizer and Moderna plan to monitor COVID-19 cases in their efficacy trials for up to two years. It is possible to identify rarer safety issues only when the vaccine has been administered to millions of people, together with long-term follow-ups and monitoring.
A lot of unknowns
Pfizer did not provide any information about the nature of COVID-19 illnesses in the 94 cases observed. Therefore, it is not possible to say if the vaccine candidate’s protection was against mild, moderate or severe forms of the disease. Moderna’s interim report reveals that its vaccine candidate was effective against severe COVID-19.
Can the vaccine candidates prevent asymptomatic infections? We don’t know. This will be important in determining their utility in containing the spread of the pandemic.
Will the vaccine candidates offer protection to the elderly? Will they protect children? Again, we have no inkling, as the ages of the COVID-19 cases in the Pfizer trial are unknown. Moderna has indicated that its candidate is effective in older people.
Do the vaccine candidates’ efficacies depend on racial and/or ethnic differences? Although about 40% of participants in the Pfizer trial are ethnically diverse, the company did not reveal their break-up among the 94 COVID-19 cases. Moderna has indicated that 20 of its 95 COVID-19 cases were among racially diverse participants.
Another important question is how long the vaccine candidates’ protection is likely to last. Would this be three months, six months or longer? It is too early to tell. Researchers can answer this question only after running the trials for several months. Doing so will also help identify any unforeseen safety issues.
For example, a dengue vaccine licensed in the Philippines, on the basis of a one-year safety monitoring report, caused severe dengue illness in a subset of children. These children had not encountered dengue infection prior to vaccination. This happened because the dengue vaccine-induced antibodies promoted the disease instead of protecting against it (which happens under certain circumstances). The vaccine developers identified this safety risk in their phase 3 trial volunteers three years after administering the dengue vaccine.
Researchers have raised the possibility of such an issue for SARS-CoV-2 infections, and they will need to carefully evaluate it.
The Pfizer/BioNTech and Moderna announcements signify remarkable milestones – coming as they did within a year of the emergence of the COVID-19 pandemic. And their preliminary (and limited) success points to the feasibility of developing vaccines against COVID-19. However, there are numerous unanswered questions at this time.
Given the raging pandemic and the promise of high efficacy, both these vaccine candidates are likely to be granted EUAs by this year’s end or in early 2021, provided nothing untoward happens. It is important to recognise that an EUA once granted will be based on the perceived promise of safety and efficacy of the interim data – and should not be treated as a full-fledged license granted on the basis of complete information gathered after the completion of phase 3 trials. Vaccine development is fraught with unknown safety risks, as the debacle in the Philippines has shown.
In addition, the hype and optimism triggered by Pfizer’s announcement fetched handsome returns to Pfizer’s CEO. The Moderna announcement has propelled the Dow Jones index to an all-time high. Companies are basically in the business of selling – and what we have at the moment are just the companies’ announcements, which have fuelled palpable excitement that COVID-19 vaccines are imminent.
But in the absence of detailed data, the optimism and hope generated by company announcements need to be tempered with caution and realism. It remains to be seen if the promise these candidates hold for curtailing the pandemic will be realised. Until then, masks, hand-washing and physical distancing are the only means to stave off SARS-CoV-2 infections.
S. Swaminathan is a retired scientist based in New Delhi.