Phase 3 Trial Data for the Pfizer-BioNTech COVID-19 Vaccine

Booster Injection Phase 3 Antibody Trial for Ages 18+

These data were presented to the FDA but have not yet been fully published in a peer-reviewed journal. Updates will be provided as further information becomes available.

A phase 3 trial for the Pfizer-BioNTech booster injection was designed to see if the booster increased participants’ levels of antibodies to the COVID-19 spike protein.¹ It was organized as a sub-study of the original phase 3 trial (see below for a summary of the original trial). The booster sub-study enrolled 306 participants who were in the original phase 3 trial. As part of that original trial, they had already received the Pfizer-BioNTech primary series of 2 injections given 21 days apart at a dose of 30 micrograms of mRNA per injection. 

For the booster sub-study, the participants received a third injection at a dose of 30 micrograms of mRNA. There was no placebo (salt water) injection group. The length of time between the second and third injections was between 5 and 6 months for 9% of the participants, between 6 and 7 months for 50%, and over 7 months for 41%. The average time between the second and third injections for the group as a whole was just under 7 months (6.8 months). 

The average age was 41.3 years. The youngest was 19 and the oldest was 55. The gender breakdown was 46% male and 54% female. The racial/ethnic breakdown was 81.4% white; 27.8% Hispanic/Latino/Latina; 9.2% Black/African-American; 5.2% Asian; 0.7% Native American or Alaskan Native; 0.3% Native Hawaiian or Pacific Islander; 1.3% multiracial; and 2.0% did not report. About 40% of the participants were obese (had a body mass index of at least 30). Participants overall had a diverse medical history profile and level of chronic diseases consistent with that of individuals in the general population and those in the original phase 3 study. 

One month after the booster shot, blood testing showed that 93.9% of the participants had developed fresh neutralizing antibodies to the COVID-19 spike protein after the booster. Neutralizing antibodies stick to the spike protein and block COVID-19 viruses from infecting human cells. The average blood level of antibodies one month after the booster dose was 3 times higher than the average blood level of antibodies observed one month after the second primary series vaccine injection. This means the booster had a powerful boosting effect on neutralizing antibody levels. 

The side effects to the booster shot were very similar to those seen after the second injection in the original phase 3 study of the primary series vaccine. These included injection site pain (83% of participants), fatigue (63.7%), headache (48.4%), muscle/joint pain (39.1%), and chills (29.1%). Most side effects were mild or moderate. Just under half of the participants chose to take an over-the-counter pain reliever/fever reducer medication. There were no cases of anaphylaxis, hypersensitivity, Bell’s palsy, appendicitis, or myocarditis/pericarditis (inflammation of the heart tissue or membrane around the heart). There were no deaths. 

Booster Injection Phase 3 Safety/Effectiveness Trial for Ages 16+

These data were presented to the FDA but have not yet been fully published in a peer-reviewed journal. Updates will be provided as further information becomes available. 

A larger phase 3 trial for the Pfizer-BioNTech booster injection was designed to see if the booster was effective for reducing the risk of getting symptomatic COVID-19 illness.² Note that the study did not test participants for asymptomatic COVID-19 infection. The definition for a “confirmed COVID-19 case” that the investigators used in this study was the presence of at least one COVID-19 symptom combined with a positive SARS-COV-2 test by polymerase chain reaction (PCR, also called a “molecular test”). 

A total of 10,125 participants were enrolled in the study from Brazil, the USA, and South Africa. All of them had been in the original phase 3 trial and so had already received the Pfizer-BioNTech primary series of 2 injections given 21 days apart at a dose of 30 micrograms of mRNA per injection. In this booster trial, half of them were randomly assigned to receive a booster dose injection of 30 micrograms of mRNA and the other half to receive a placebo (salt water) injection. The booster injection or placebo injection was given at a minimum of 6 months after the second primary series injection; the average time between was 10 months. 

There were 2 age groups in this study. Approximately 60% of participants were between 16 and 55 years of age, and approximately 40% were older than 55 years of age. Overall, the average age for the entire study population was 51.7 years. The youngest participant was 16 and the oldest was 87. The gender breakdown was 49.1% male and 50.9% female. The racial/ethnic breakdown was 79% white; 14.9% Hispanic/Latino/Latina; 9.2% Black/African-American; 5.5% Asian; 1.7% Native American or Alaskan Native; 0.2% Native Hawaiian or Pacific Islander; 4.0% multiracial; and 0.6% did not report. Chronic conditions and diseases were common among the study participants and were similar in nature to those in the primary vaccine series phase 3 study.

The booster injection was very effective in this study. In the vaccine group, there were 6 cases of confirmed COVID-19 disease that happened between 7 days and 2 months after the booster injection. In the placebo group, there were 123 cases of confirmed COVID-19 disease that happened between 7 days and 2 months after the placebo (salt water) injection. This corresponds to 95.3% vaccine efficacy. The authors looked at the vaccine efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition as well. The efficacy rate was between 91.8% and 100% for these various subgroups.

The researchers also looked at severe COVID-19 disease. Two participants had severe COVID-19 illness, and both received placebo (salt water) injection. These participants did not need to be hospitalized but had an oxygen saturation of less than 93% on room air. There were no hospitalizations or deaths in this study for COVID-19 disease.

The investigators reported that side effects were similar to those seen in the primary series vaccine phase 3 trial (see below). About 25% of participants in the booster injection group had side effects, and most were mild. About 6% of participants in the placebo injection group had side effects, and most were mild. There were no hospitalizations in the booster injection group for side effects. 

Primary Series (Two-Dose Injection) Phase 2/3 Safety/Effectiveness Trial for Ages 5-11

These data were presented to the FDA but have not yet been fully published in a peer-reviewed journal. Updates will be provided as further information becomes available. 

A phase 2/3 trial was designed to test the safety and effectiveness of the COVID-19 primary series (two-dose injection) vaccine in children 6 months to 11 years of age.³ The dose chosen for this study was 10 micrograms of mRNA per injection. This dose decision was based on a small phase 1 safety study in 48 participants that tested 3 different dose levels for side effects (10, 20, or 30 micrograms of mRNA per injection). 

In the phase 2/3 study, 2,268 participants who were 5 to 11 years of age were enrolled from 90 clinics in the United States, Finland, Poland, and Spain. A total of 1,518 children received 2 vaccine injections, while 750 children received 2 placebo (salt water) injections. In both groups, the injections were 21 days apart.

The study population was 52.1% male and 47.9% female. The average age was 8.2 years. The racial/ethnic breakdown was 78.9% white; 21.1% Hispanic/Latino/Latina; 6.5% Black/African-American; 6.0% Asian; 0.4% Native American or Alaskan Native; and 7.0% multiracial. Obesity was seen in 11.7% of the children, and was defined as a body mass index (BMI) at or above the 95th percentile according to The Centers for Disease and Control and Prevention standard pediatric growth charts. About 21% had at least one underlying medical condition, such as cardiovascular disease, sickle cell anemia, need for a feeding tube, being immunocompromised, chronic lung disease, asthma, or neurological disease.

The definition for a “confirmed COVID-19 case” that the investigators used in this study was the presence of at least one COVID-19 symptom combined with a positive SARS-COV-2 test by polymerase chain reaction (PCR, also called a “molecular test”).

The vaccine was highly effective for preventing symptomatic COVID-19 disease in this age group. Counting from 7 days after the second dose, there were 3 cases of COVID-19 illness in the vaccine group and 16 cases in the placebo. This indicates an effectiveness of 90.7% Antibody levels to COVID-19 spike protein were very high among vaccinated children and were similar to the average level seen for participants in the original phase 3 trial who were aged 16 to 25 years. There were no serious cases of COVID-19, no hospitalizations, and no deaths in either group. 

Side effects to the vaccine were similar to those seen in the phase 3 trials for ages 16 years and older and for ages 12 to 15 years. There was a small increase in side effect frequency after the second injection compared to the first. After the second injection, the most common side effects were pain at the injection site (71.0% in the vaccine group and 29.5% in the placebo group), redness at the injection site (18% and 5.4%), swelling at the injection site (15.3% and 2.7%), fatigue (39.4% and 24.3%), headache (28.0% and 18.6%), muscle pain (11.7% and 7.4%), chills (9.8% and 4.3%), fever (6.5% and 1.2%), diarrhea (5.3% and 4.7%), joint pain (5.2% and 3.6%), and vomiting (1.9% and 0.8%). Most of these side effects were mild or moderate, lasted less than 2 days, and could be managed by taking over-the-counter pain relievers/fever reducers.

There were no serious adverse events related to the vaccine or placebo injections. There were no cases of anaphylaxis, myocarditis/pericarditis (inflammation of the heart or sac around the heart), Bell’s palsy (paralysis of the facial muscles), or appendicitis.

Primary Series (Two-Dose Injection) Phase 3 Safety/Effectiveness Trial for Ages 12-15 

These data were presented to the FDA but have not yet been fully published in a peer-reviewed journal. Updates will be provided as further information becomes available. 

After early safety results from the primary series (two-dose injection) phase 3 safety/effectiveness trial (see below) were available, the trial was expanded to include participants aged 12 to 15 years.⁴ All participants in this age group were from the United States. A total of 1,131 participants received two 30-microgram doses of the COVID-19 vaccine given 21 days apart, and another 1,129 participants received placebo injections. 

The study population was 50.9% male and 49.1% female. The racial/ethnic breakdown was 85.5% white; 11.6% Hispanic/Latino/Latina; 4.8% Black/African-American; 6.4% Asian; 0.4% Native American or Alaskan Native; 0.1% Native Hawaiian or Pacific Islander; 2.3% multiracial; and 0.6% did not report.

The definition for a “confirmed COVID-19 case” that the investigators used in this study was the presence of at least one COVID-19 symptom combined with a positive SARS-COV-2 test by polymerase chain reaction (PCR, also called a “molecular test”).

The vaccine was 100% effective at preventing symptomatic COVID-19 illness in this age group. Counting from the seventh day onward after the second injection, the number of confirmed COVID-19 cases was 0 in the vaccine group and 16 in the placebo group during the follow-up time. The follow-up time ranged from 1 to 3 months, with most patients having a follow-up time of somewhere between 2 to 3 months. None of the COVID-19 cases in the placebo group were severe, and no one was hospitalized. 

The investigators also checked antibody levels against the COVID-19 spike protein for each participant 1 month after the second injection. The average level was very high, about 75% higher than the average level seen for participants in the original phase 3 trial who were aged 16 to 25 years. This indicates that adolescents have a more robust immune response to the vaccine, on average, than young adults do. 

There were some side effects in the study that were similar to those seen in the original phase 3 trial in ages 16+ (see below). The side effects were more common after the second injection. After the second injection, the most common side effects were pain at the injection site (78.9% in the vaccine group and 17.9% in the placebo group), fatigue (66.2% and 24.5%), headache (64.5% and 24.4%), chills (41.5% and 6.8%), muscle pain (32.4% and 8.3%), fever (19.6% and 0.6%), joint pain (15.8% and 4.7%), diarrhea (5.9% and 4.0%), vomiting (2.6% and 1.1%), lymphadenopathy/swollen lymph nodes or “swollen glands” (0.8% and 0.2%). There were no serious adverse events in either the vaccine or placebo groups. There were no deaths. 

Primary Series (Two-Dose Injection) Original Phase 3 Safety/Effectiveness Trial for Ages 16+ (Updated with Pregnancy Data)  

In this initial phase 3 trial, the researchers investigated the safety and efficacy of two 30-microgram doses of the COVID-19 vaccine given 21 days apart, as compared with placebo injections (salt water).⁵ Participants in the trial were recruited from 152 sites worldwide: United States (130 sites); Argentina (one site); Brazil (2 sites); South Africa (4 sites); Germany (6 sites); and Turkey (9 sites). Adults 16 years of age or older could enroll in the study. People who already had COVID-19 disease were not included in the trial. In addition, people who were undergoing immunosuppressive therapy or who had an immunocompromising condition were not included in the trial.

A total of 21,720 participants received the vaccine and 21,728 received placebo. The median age was 52 years. The youngest participants were 16 years old and the oldest was 91 years old. The gender breakdown was 50.6% male and 49.4% female. The racial/ethnic breakdown was 82.9% white; 28.0% Hispanic/Latino/Latina; 9.3% Black/African-American; 4.3% Asian; 0.5% Native American or Alaskan Native; 0.2% Native Hawaiian or Pacific Islander; 2.3% multiracial; and 0.6% did not report. 

About 35% of the participants were obese (had a body mass index of at least 30). About 21% of the participants had at least one chronic condition. The most common chronic medical conditions in the study population were chronic pulmonary disease (7.8%), uncomplicated diabetes (7.8%), any type of cancer/malignancy (3.7%), cerebrovascular disease (1.0%) and history of heart attack (1.0%). Other chronic conditions were present in less than 1% each, including HIV positive status, heart failure, liver disease, rheumatic disease, peptic ulcer, and kidney disease. 

The definition for a “confirmed COVID-19 case” that the investigators used in this study was the presence of at least one COVID-19 symptom combined with a positive SARS-COV-2 test by polymerase chain reaction (PCR, also called a “molecular test”). 

The vaccine was very effective in this study. In the vaccine group, there were 9 cases of confirmed COVID-19 disease that happened 7 days or later after the second dose of vaccine. In the placebo group, there were 169 cases of confirmed COVID-19 disease that happened 7 days or later after the second “dose” of placebo. This corresponds to 94.6% vaccine efficacy. The authors looked at the vaccine efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition as well. The efficacy rate was between 89.3% and 100% for these various subgroups. 

Between the first dose and the second dose, 39 cases of confirmed COVID-19 disease were seen in the vaccine group and 82 cases in the placebo group, for a vaccine efficacy of 52% during the time between the 2 doses. 

The researchers also looked at severe COVID-19 disease. Four participants had severe COVID-19 disease at least 7 days after the second injection. One was in the vaccine group and 3 were in the placebo group. The person in the vaccine group with severe disease did not need to be hospitalized but had an oxygen saturation of 93% on room air. The 3 placebo recipients who had severe COVID-19 disease met the severe case definition for the following reasons: one had an oxygen saturation of 92% on room air, one was hospitalized with bilateral pneumonia, and one had an oxygen saturation of 92% and was admitted to the ICU admission for heart block. 

There were some side effects in the study, as is commonly seen with vaccines. The side effects were more common after the first injection rather than the second injection. They were also more common in younger participants (16 years to 55 years) than in older participants (over 55 years). 

The information below about pain, redness, and swelling is about the first injection in younger participants (16 years to 55 years) because that is when the highest number of side effects happened. The most common side effect was pain at the injection site in the arm, which 83% of the vaccine group and 14% of the placebo group reported. The pain was generally mild to moderate and lasted 1 to 2 days. Only 1% of the vaccine group reported the pain as severe. Redness at the injection site was reported by 4.7% of the vaccine group and 1.1% of the placebo group. Swelling at the injection site was reported by 5.8% of the vaccine group and 0.5% of the placebo group. 

Other side effects were fever, chills, headache, fatigue and body aches. These were more common after the second injection, rather than the first, and were more common in younger participants than in older participants. These effects usually lasted 1 to 2 days and were managed with over-the-counter pain relievers/fever reducers. The information below is about these side effects after the second injection in younger participants: fever (15.8% of the vaccine group and 0.5% of the placebo group); fatigue (59.4% and 22.8%); headache (51.7% and 24.1%); chills (35.1% and 3.8%); muscle pain (37.3% and 8.2%); diarrhea (10.4% and 8.4%) and vomiting (1.9% and 1.2%). 

There were 2 serious adverse events in the vaccine group that the FDA considered may have been related to the vaccine: a shoulder injury possibly related to vaccine administration or to the vaccine itself and a case of severely swollen glands in the armpit. There were 4 cases of Bell’s palsy (facial paralysis) in the vaccine group and none in the placebo group. These symptoms have all resolved. It is unclear if these cases are related to the vaccine, because Bell’s palsy occurs in the general population at about the same rate. The FDA will be monitoring this reaction carefully. 

There were 89 pregnancies among the participants in this phase 3 study, with 42 in the vaccine group and 47 in the placebo group. Among these, there were 3 miscarriages in the vaccine group and 5 miscarriages in the placebo group. There were no birth defects or fetal deaths in either group.⁶