The Pfizer vaccine is being developed and produced by Pfizer, Inc. and the biotech company BioNTech SE. It is a genetic mRNA vaccine (mRNA-1273) currently in Phase 3 clinical trials across the globe. Here is a breakdown of everything you need to know so far about this vaccine’s development.
**Collaborators: **Biopharmaceutical company Pfizer Inc, based in New York City, and BioNTech, biotechnology company based in Mainz, Germany, are collaborating on vaccine development and testing for the mRNA-based vaccine candidate BNT162b2.
**Latest information on how well the vaccine works:** On November 30, 2020 with primary efficacy analysis data from its Phase 3 trial, Pfizer announced its experimental COVID-19 vaccine to be 95% effective 28 days after the first of two doses.
Out of approximately 44,000 total study participants, 170 contracted COVID-19. 162 who got infected were from the placebo group—meaning they didn’t receive the vaccine—and only 8 who got infected were in the group that was vaccinated with the Pfizer vaccine.
Ten of the COVID-19 cases were severe. Nine of those people were from the placebo group. One severe case was in the vaccinated group. This suggests the vaccine has high protection for severe COVID-19 cases, at 95% efficacy, meaning that if 100 study participants were the vaccine doses, 95 patients would not contract the disease and 5 would.
There have been no reported COVID-19-related deaths in the study. These new results of 95% efficacy are higher than the vaccine’s first interim analysis conducted during the study (announced on November 9th, 2020), which reported 90% efficacy based on an analysis of 94 COVID-19 cases among trial participants.
Based on a study published in February 2021 in the New England Journal of Medicine, the Pfizer-BioNTech vaccine was found to appear to be highly effective against the more transmissible variant of the virus first detected in the U.K. (B.1.1.7) (virtually no drop from 95% efficacy). However, the vaccine showed a decreased ability to neutralize the strain first detected in South Africa (B.1.351). Specifically, they found that there was about a two-thirds drop in neutralization power (antibody power) against this variant compared to other forms of the SARS-CoV-2 coronavirus.
It’s important to note that the vaccine was still able to neutralize the virus, and likely still may protect individuals from getting severe forms of the virus. In addition, these are initial lab experiments that are difficult to extrapolate results from.
Pfizer has said that evidence is needed to understand how the vaccine works against the variant in real life. The company stated, "Nevertheless, Pfizer and BioNTech are taking the necessary steps, making the right investments, and engaging in the appropriate conversations with regulators to be in a position to develop and seek authorization for an updated mRNA vaccine or booster once a strain that significantly reduces the protection from the vaccine is identified.”
**Approvals:** As of December 2, 2020, the U.K. authorized the distribution of Pfizer and BioNTech’s COVID-19 mRNA vaccine BNT162b2 for emergency supply, making the vaccine the first in the world to achieve authorization for COVID-19. Two days following the U.K.’s authorization, Bahrain approved the emergency use of the Pfizer and BioNTech vaccine, making it the second country in the world to do so. Five days following on December 9, Canada’s regulatory agency Health Canada approved the vaccine. On Friday, December 11, 2020, the U.S. Food and Drug Administration (FDA) authorized the Pfizer and BioNTech vaccine. Soon after, Pfizer and BioNTech bega rolling review processes with other global regulatory bodies, including in the U.S., Europe, Australia and Japan, and has been submitting applications to other regulatory agencies around the world, primarily in the Global North, with a range of approvals.
**Distribution timeline:** Following the U.K.’s emergency approval on December 2, 2020, the companies began delivering the first doses to the U.K. nearly immediately, starting on December 8, 2020. Canada is set to receive 249,000 doses before the end of December to distribute across 14 different vaccination sites throughout Canadian cities. Following the U.S. approval of the vaccine on December 11, 2020, the U.S. will initially distribute approximately 2.9 million doses to all 50 states.
The distribution timeline for other countries undergoing the approval process will depend on the distribution decisions made by regulators there. Some countries are already coordinating pre-approval distribution and in many of these regions and countries, logistics surrounding the supply chain of the vaccine are being decided upon and run through so that when there is an approval, distribution can begin immediately.
**Distribution plan:** In projections, Pfizer hopes to produce and supply up to 25 million vaccine doses in 2020 and 100 million doses before the start of March, with an estimated total distribution of up to 1.3 billion doses in 2021. Four of Pfizer’s facilities are part of the manufacturing and supply chain; St. Louis, MO; Andover, MA; and Kalamazoo, MI in the U.S.; and Puurs in Belgium. BioNTech’s German sites will also be leveraged for global supply. Each of these sites are important links in a global supply chain being assembled to tackle the massive logistical challenge of distributing COVID-19 vaccines around the world.
Jurisdictions primarily have the responsibility of determining who receives the vaccine in what order. For instance, within the U.S. each state will receive a certain number of doses of the vaccine based on residential populations. States have been asked to create their own plans for who will get the first doses.
In the U.K., British front-line health-care workers, as well as care-home staff and residents, are receiving the first doses. Bahrain has said that they plan to inoculate everyone 18 years and older at 27 different medical facilities, hoping to be able to vaccinate 10,000 people a day; so far, they have the second-highest vaccination rate in the world behind Israel. In general, the most likely distribution plan is for the vaccine to first go to emergency department clinicians, outpatient clinicians, testers at symptomatic sites, other high-risk health care workers, immunocompromised individuals, EMTs, and potentially essential federal employees, followed by the rest of the general population.
Vaccination distribution in some countries is moving more slowly than anticipated. In the U.S, for example, just 2.6 million individuals were vaccinated by December 31, 2020 compared to the 20 million goal by the end of 2020. In response, scientists and public health practitioners are considering vaccination tactics that differ from those that the FDA and other country’s health regulatory bodies approved. The tactics being considered are primarily halving doses of vaccines and delaying second doses to get first doses to more individuals, but also include reducing the number of doses and mixing and matching doses.
Health officials in the UK have already decided to delay second doses of two vaccines, one made by AstraZeneca and one made by Pfizer and BioNTech, and to mix and match the two vaccines for the two doses under limited circumstances. This decision has received mixed responses from scientists and public health practitioners, many of whom are concerned about the lack of data, particularly with regards to a mix-and-match approach.
The U.S. FDA critiqued the idea of halving the doses of the Moderna vaccine, saying that the idea was “premature and not rooted solidly in the available science.” Studies are underway to determine whether doses of the Moderna COVID-19 vaccine can be halved to 50 micrograms in order to double the supply of the vaccination doses in the U.S., according to the National Institutes of Health and Moderna.
**Vaccine storage conditions:** Storage requirements are important to consider for new vaccines. In order for vaccines to be safe and effective, they must be held at the correct temperature during distribution and storage in health centers, pharmacies, and clinics. Maintaining the correct storage temperature can be difficult, especially if the vaccine’s temperature requirement is very cold.
The Pfizer and BioNTech vaccine can be stored for five days at refrigerated 2-8°C (36-46°F) conditions (refrigerators that are commonly available at hospitals); up to 15 days in Pfizer thermal shippers in which doses will arrive that can be used as temporary storage units by refilling with dry ice; and up to 6 months in ultra-low-temperature freezers, which are commercially available and can extend the vaccine’s shelf life.
With regards to transit, Pfizer is using dry ice to maintain the recommended temperature conditions of -70°C±10°C (-94°F) for up to 10 days while in transit. However, Pfizer and BioNTech have determined that the vaccine can be moved only four times.
**Type of vaccine:** The mRNA-1273 vaccine is what scientists are calling a genetic mRNA vaccine. This type of vaccine works by using genetic information from the coronavirus, which is injected into the body. The genetic information enters into human cells, instructs the body to make special spike proteins like the coronavirus, and causes the immune system to respond.
**Dosage:** In the current Phase 3 clinical trial, participants receive two injections of 30 micrograms each into their upper arm muscle. The injections are given 21 days apart. Once an individual gets the first dose, they must get the second dose three weeks later in order to complete the vaccination. If approved, researchers expect that the same dosage and schedule will be prescribed to the public.
A recent Israeli study that released results in February 2021 by the Lancet found that a single dose of the Pfizer vaccine was 85% effective against COVID-19 infection between two and four weeks after the first dose, and that the overall reduction in infections was 75%, including asymptomatic cases. Public health practitioners are enthusiastic about this finding of high efficacy after just one dose; However, the authors cautioned that the low numbers of COVID-19 cases in the study, and the fact that the study was conducted at one hospital, make it difficult to reach exact estimates and that these findings should be interpreted with caution. The study also does not determine the length of protection. Pfizer did not comment on the data, stating that “the vaccine’s real-world effectiveness in several locations worldwide, including Israel.”
Studies out of the U.K., which has been the quickest to inoculate its population, have also found that a single dose of the Pfizer vaccine could avert most COVID-19-related hospitalizations, though investigators stated it was too early to give precise estimates of the effect.
**How the vaccine is being studied:** Vaccines are tested and studied in multiple phases (phased testing) to determine if they are safe and work to prevent illness. Before a vaccine is tested on humans, which is known as the preclinical phase, it is tested on laboratory cells or animals. Once it is approved for human research, there are three phases that take place before the vaccine can be considered for approval for public use. During the first stage (Phase I), the new vaccine is provided to small groups of people—the first time the vaccine is tested in humans to test safety (primarily) and efficacy of the vaccine.
The second stage (Phase II) involves testing the vaccine on people who have similar characteristics (such as age and physical health) to the target population, or the group for which the vaccine is intended. The goal of this stage is to identify the most effective doses and schedule for Phase III trials. The final stage (Phase III) provides the vaccine to thousands of people from the target population to see how safe and effective it is.
Once the vaccine has undergone Phase 3 testing, the manufacturer can apply for a license from regulatory authorities (like the FDA in the US) to make the vaccine available for public use. Once approved, the drugmaker will work with national governments and international health organizations to monitor vaccine recipients for potential side effects from the vaccine that were not seen in clinical trials (this is called surveillance). This phase also helps researchers understand how well a vaccine works over a longer time frame and how safe it is for the population.
**How Pfizer looked for COVID-19 cases in their trials:** Researchers have standard definitions for routinely detecting COVID-19 cases for both symptomatic and asymptomatic individuals. For symptomatic individuals, there are three definitions considered for defining a COVID-19 case for the study. The first two are for regular cases, and the third is for severe cases.
The first definition is the presence of at least one COVID-19 symptom and a
positive COVID-19 test (such as a PCR test) during, or within 4 days before or after, the symptomatic period, either at the central laboratory or at a local testing facility. The second definition is the same, but expands the definition to include four additional COVID-19 symptoms defined by the CDC (fatigue; headache, nasal congestion or runny nose, nausea). The third definition, which defines severe COVID-19 cases for the study, is a confirmed COVID-19 test per the above guidelines in addition to one of the following symptoms: clinical signs at rest indicative of severe systemic illness, respiratory failure, evidence of shock, significant acute renal, hepatic, or neurologic dysfunction, admission to an ICU, or death. The Pfizer research protocol states that for individuals who do not clinically present COVID-19 (that is, asymptomatic individuals), a serological test is used for defining a case, which measures the amount of antibodies or proteins present in the individual’s blood, and a positive case is defined as the presence of antibodies in an individual who had a prior negative test.
By using these four definitions, researchers are able to detect COVID-19 cases in both symptomatic and asymptomatic individuals. However, the pharmaceutical company has stated that there are more data on the vaccine’s safety and efficacy for symptomatic cases, and that more data is needed to better understand the vaccine’s safety and efficacy for asymptomatic cases.
**Preclinical testing:** Before testing could begin on humans, the trial vaccine was tested on primates at both 30 micrograms and 100 micrograms. On September 9, 2020, results were published demonstrating that the Pfizer vaccine had strong antiviral protection against the virus SARS-CoV-2. As a result, the Pfizer and BioNTech were permitted to advance the vaccine into human clinical trials by the FDA in the form of through the Investigational New Drug application (IND).
**Phase 1 trial:** 45 healthy adults 18–55 and 65–85 years old were randomly assigned to either the placebo group or the vaccine group to receive 2 doses at 21-day intervals of placebo or either of 2 mRNA-based vaccines (BNT162b2 or BNT162b1, which was one of several RNA-based SARS-CoV-2 vaccines studied in parallel for selection to advance to a next trial). Participants received either 10, 20, or 30 microgram dose levels of BNT162b1, or BNT162b2 on a 2-dose schedule, 21 days apart. Both participants and observers working on the study were “blinded,” or not aware of which participants were receiving the active vaccines (and which ones) versus the treatment, in order to help prevent bias.
Both with 10 micrograms and 30 micrograms of vaccine BNT162b1, and t 7 days after a second dose of 30 micrograms of the BNT162b2 vaccine, “SARS-CoV-2–neutralizing antibodies” were elicited—special proteins that disable viruses in the body—in younger adults (18-55 years of age) and older adults (65-85 years of age). Younger participants had 3.8 times more antibodies than people who had recovered from the virus. In older adults (65-85 years of age) the vaccine candidate triggered antibodies at 1.6 times the volume of those who had recovered from the virus in the same age group. Vaccine BNT162b2, now known as the “Pfizer vaccine,” was associated with fewer reactions (such as fever and chills), and was therefore selected for Phase 2/3 trials.
In terms of safety and tolerability of vaccine BNT162b2, reactions were still reported. Study participants reported pain at the injection site, headache, fatigue, muscle pain, chills, joint pain, and fever. Most of these reactions and symptoms peaked by the day after vaccination and resolved by day 7.
**Phase 2/3 trial: **In an effort to speed up the trial, Phases 2 and 2 of the Pfizer vaccine were combined. This phase continued off of Phase 1 and also contained a placebo group as a control with patients randomly assigned into either the placebo group or vaccine group for vaccine BNT162b2. As with Phase 1, the observers and participants were also “blinded.” The first 360 participants enrolled made up the “Phase 2” portion, with 180 randomly assigned to receive the active vaccine and 180 to receive the placebo, stratified equally between 18 to 55 years and >55 to 85 years. Phase 3 enrolled 43,538 trial participants overall, half of whom were randomly assigned to receive the vaccine and half of whom were randomly assigned to receive the placebo. Out of 170 cases of COVID-19 among the study participants,162 cases of COVID-19 were observed in the placebo group versus 8 cases in the vaccine group, indicating 95% efficacy of the vaccine. No serious safety concerns were observed. Data collection is ongoing.
**Reported side effects and safety concerns:** The study’s Data Monitoring Committee did not report any serious safety concerns related to the vaccine based on the trial data. Adverse events at or greater than 2% in frequency that were reported were fatigue at 3.8% and headache at 2.0%. Potential allergic reactions occurred in 0.63% of those who received the vaccine, compared with 0.51% of those who received the placebo.
On December 9, one day after the Pfizer and BioNTech vaccine began being distributed to individuals outside of the clinical trial in the UK, UK regulators advised that individuals with a history of anaphylaxis to a vaccine, medication, or food should not receive the vaccine. This warning was issued in response to two reports of anaphylaxis (severe allergic reaction) -- both among individuals with histories of severe allergies -- and one report of a possible allergic reaction since distribution in the UK began. Pfizer and BioNTech have stated that they are working with investigators to better understand the cases and causes of the reactions.
Within the clinical trial, individuals with a history of severe allergic reactions were excluded from the trials, and doctors were asked to look for such reactions in trial participants who weren’t previously known to have severe allergies. UK regulators also required health care workers to report any negative reactions to help regulators collect more information about safety and effectiveness.
In addition, four people who received the vaccine during trials later developed Bell’s palsy at 3, 9, 37, and 48 days after vaccination, respectively. Because these trials were so large, however, this is not more than we would expect to develop Bell’s palsy in a group of this size by chance. Bell’s palsy is a weakness or paralysis of one side of the face which is usually temporary. Any cases of Bell’s palsy and any other potential side effects or adverse reactions will continue to be monitored and evaluated for as the vaccine continues to be rolled out to the public.
**Impact on different populations:** Pfizer and BioNTech both say they aimed to make their trials as diverse as possible to understand the vaccine’s effect on different populations. The trial participants are approximately 30% U.S. participants and 42% non-U.S. participants from across 150 trial sites globally. The participants are reported to have racially and ethnically diverse backgrounds. In the trials, 41% of global and 45% of U.S. participants are 56-85 years of age. Efficacy was reported to be consistent across age, gender, race and ethnicity demographics.
Notably, the observed efficacy in individuals over 65 years of age was observed to be greater than 94%. In September 2020, Pfizer and BioNTech expanded Phase 3 enrollment to approximately 44,000 participants. This expansion allowed for the enrollment of new, more diverse, populations, including adolescents as young as 16 years of age, and individuals with chronic, stable human immunodeficiency viruses (HIV), Hepatitis C, or Hepatitis B infection. In October 2020, Pfizer and BioNTech received permission from the FDA to enroll adolescents as young as 12. Their explanation for these expansions is to enable better understanding of the potential safety and efficacy of the vaccine in individuals from more ages and backgrounds.
**Other relevant notes:** N/A