Novavax COVID-19 Vaccine Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events

Persons Aged 12-17 years

Local Reactions

Local reactions were reported by the majority of vaccine recipients and at higher rates than placebo recipients (75.3% vs 20.6% after dose 2). Pain/tenderness at the injection site was the most common and most severe local reaction among vaccine recipients and reported more frequently after dose 2 than after dose 1. Injection site redness and swelling following either dose were reported less frequently but were more common after dose 2 than dose 1. There were no grade 4 local reactions reported. Overall the median time to onset for local reactions was 1-3 days. The median duration of local reactions was 1-3 days in the vaccine group. (Table 1).

Table 1. Local reactions in persons ages 12-17 years, Novavax NVX-CoV2373 COVID-19 vaccine and placebo

^a Grade 3: > 10 cm; and Grade 4: Necrosis or exfoliative dermatitis (redness only)

^b Grade 3: Any use of narcotic pain reliever or prevents daily activity; and Grade 4: ER visit or hospitalization.

^c Grade 3: Significant discomfort at rest; and Grade 4: ER visit or hospitalization.

Systemic Reactions

Systemic reactions were reported by the majority of vaccine recipients and at higher rates than placebo recipients. The frequency of systemic reactions was higher after dose 2 than dose 1 (74.5% vs 55.3%); the severity of systemic reactions was also higher after dose 2 than dose 1 (3.7% vs 22.0% reporting reactions of grade 3 or higher). Fatigue/malaise were the most common systemic reaction (57.9% after dose 2). Fever was reported by 16.9% of vaccine recipients following dose 2. The majority of systemic reactions were mild or moderate in severity. Following Dose 2, 21.8% of participants reported any severe systemic reaction; the most frequently reported severe systemic reactions were fatigue/malaise and myalgia. Grade 4 fever (>40.0°C) was reported by two vaccine recipients after dose 1. Following dose 2, there was one report of grade 4 headache and one report of grade 4 nausea/vomiting among vaccine recipients. For systemic reactions, the median time to onset was between 1 and 3 days after vaccination and persisted for 1-2 days. (Table 2)

Table 2. Systemic reactions in persons aged 12-17 years, Novavax NVX-CoV2373 COVID-19 vaccine and placebo

^a Grade 3: 39.0 to 40°C/102.1 to 104°F; Grade 4: >40°C/ >104°F.

^b Grade 3: Significant; prevents daily activity; Grade 4: ER visit or hospitalization.

^c Grade 3: Significant; any use of narcotic pain reliever or prevents daily activity; Grade 4: ER visit or hospitalization.

^d Grade 3: Prevents daily activity, requires outpatient intravenous (IV) hydration; Grade 4: ER visit or hospitalization for hypotensive shock.

Unsolicited Adverse Events

Unsolicited adverse events were collected from dose 1 to 28 days post-dose 2. Frequencies of unsolicited adverse events were similar between the vaccine group (15.5%) and placebo group (15.3%). The most frequently reported (>1.0%) unsolicited AEs among vaccine recipients were consistent with common conditions in adolescents, including nasal congestion, cough, and oropharyngeal pain. Non-serious unsolicited AEs considered related by the investigator were reported by 2.9% of participants in the vaccine arm and 0.8% of participants in the placebo arm. The most frequently reported related AEs in the vaccine arm included lymphadenopathy-related events, chills, diarrhea, and decreased appetite. Additional related adverse events were consistent with local and systemic reactogenicity. Lymphadenopathy-related events (lymphadenopathy, axillary pain, and lymph node pain) were reported by 0.9% of participants in the vaccine arm and 0% of participants in the placebo arm and are considered plausibly related to vaccination. A plausible biological mechanism and imbalances in the following additional non-serious unsolicited events are suggestive of a causal relationship to vaccine: fatigue (0.5% vaccine recipients vs. 0.0% placebo recipients), decreased appetite (0.3% vaccine recipients vs. 0.0% placebo recipients), arthralgia (0.2% vaccine recipients vs. 0.0% placebo recipients), injection site pruritus (0.2% vaccine recipients vs. 0.0% placebo recipients), and myalgia (0.1% vaccine recipients vs. 0.0% placebo recipients).

Serious Adverse Events

A serious adverse event was defined as: death; life-threatening event; hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or a congenital anomaly/birth defect. Serious adverse events were reported by 7 vaccine recipients (0.5%) and 2 placebo recipients (0.2%). FDA determined that none of the events following vaccination were related to study vaccine.

A 16-year-old male experienced myocarditis two days after dose 2 of the post-crossover period of the trial. Based on the timing of onset following vaccination and multiple similar cases of temporally related myocarditis and pericarditis, FDA considers this event related to the vaccine.

Persons Aged ≥ 18 Years

Local Reactions

Local reactions were reported by the majority of vaccine recipients and at higher rates than placebo recipients. Vaccine recipients reported higher rates of local reactions after dose 2 than dose 1. The frequency of local reactions was higher in the 18–64 age group than the ≥65 age group (80.9% vs 61.7% after dose 2). Pain/tenderness at the injection site was the most frequent and severe reported solicited local reaction among vaccine recipients. After dose 1, the 18–64 age group reported pain/tenderness more frequently than the ≥65 age group (60.5% vs 37.9%); a similar pattern was observed after dose 2 (80.8% vs 61.4%). Five grade 4 local reactions of pain/tenderness were reported after dose 2. Redness and swelling were reported less frequently, but these reactions were also more common after dose 2. Overall, the median onset of local reactions in the vaccine group was 2 days after either dose, with a median duration of 2 days after dose 1 and 3 days after dose 2. (Table 3, Table 4).

Table 3. Local reactions in persons aged 18-64 years, Novavax COVID-19 vaccine and placebo

^a Grade 3: Any use of narcotic pain reliever or prevents daily activity; and Grade 4: Emergency room visit or hospitalization.

^b Grade 3: Significant discomfort at rest; Grade 4: ER visit or hospitalization.

^c Grade 3: >10 cm; Grade 4: Necrosis or exfoliative dermatitis.

^d Evaluated and graded using the functional scale as well as the actual measurement; Grade 3: >10 cm or prevents daily activity; Grade 4: Necrosis.

Table 4. Local reactions in persons aged ≥65 years, Novavax COVID-19 vaccine and placebo

^a Grade 3: Any use of narcotic pain reliever or prevents daily activity; and Grade 4: Emergency room visit or hospitalization.

^b Grade 3: Significant discomfort at rest; Grade 4: ER visit or hospitalization.

^c Grade 3: >10 cm; Grade 4: Necrosis or exfoliative dermatitis.

^d Evaluated and graded using the functional scale as well as the actual measurement; Grade 3: >10 cm or prevents daily activity; Grade 4: Necrosis.

Systemic Reactions

Systemic reactions were reported at higher rates than placebo recipients for both age groups and after both doses. The frequency of systemic reactions was higher in the 18-64 age group than the ≥65 age group (72.1% vs 48.7% after dose 2). Within each age group, the frequency and severity of systemic reactions was higher after dose 2 than dose 1. For both age groups, fatigue/malaise, headache and muscle pain were the most commonly reported systemic reactions. The majority of systemic reactions were mild or moderate in severity, after both doses and in both age groups. Fever was more common after the second dose and in the younger group (6.2%) compared to the older group (2.0%). Among vaccine recipients, the median onset of systemic reactions was 2 days after either dose, with a median duration of 1 day. Grade 4 fever (>40.0°C) was reported by four vaccine recipients after dose 1 and two vaccine recipients after dose 2. Grade 4 systemic reactions after dose 1 and dose 2 in the 18–64 age group were: headache, fatigue, muscle pain, joint pain, nausea/vomiting, and malaise; see table 3 for details. One report of grade 4 headache after dose 1 and one report each of grade 4 headache and grade 4 joint pain were reported after dose 2 in the ≥65 age group (Table 5, Table 6)

Table 5. Systemic reactions in persons aged 18-64 years, Novavax COVID-19 vaccine and placebo

^a Any: ≥38.0°C/100.4°F; Grade 3: 39.0 to 40°C/102.1 to 104°F; Grade 4: >40°C/>104°F.

^b Grade 3: Significant; any use of narcotic pain reliever or prevents daily activity; Grade 4: ER visit or hospitalization.

^c Significant; prevents daily activity; Grade 4: ER visit or hospitalization.

^d Grade 3: Prevents daily activity, requires outpatient IV hydration; Grade 4: ER visit or hospitalization for hypotensive shock.

Table 6. Systemic reactions in persons aged ≥65 years, Novavax COVID-19 vaccine and placebo

^a Any: ≥38.0°C/100.4°F; Grade 3: 39.0 to 40°C/102.1 to 104°F; Grade 4: >40°C/>104°F.

^b Grade 3: Significant; any use of narcotic pain reliever or prevents daily activity; Grade 4: ER visit or hospitalization.

^c Significant; prevents daily activity; Grade 4: ER visit or hospitalization.

^d Grade 3: Prevents daily activity, requires outpatient IV hydration; Grade 4: ER visit or hospitalization for hypotensive shock.

Unsolicited Adverse Events

Unsolicited AEs were collected from after the first vaccination through 28 days after dose 2. A higher frequency of unsolicited adverse events was reported in the vaccine group compared to the placebo group and was primarily attributed to local and systemic reactogenicity following vaccination. There was a higher frequency of unsolicited AEs among vaccine recipients in the older age group (22.7%) compared to the younger age group (18.3%). Imbalances were observed in multiple categories: cardiac failure and cardiomyopathy (0.05% in vaccine group and 0.02% in placebo arm); events consistent with stroke (0.06% in vaccine group and 0.02% in placebo group [3 of 11 events occurred within 15 days of most recent vaccine dose]); pulmonary embolism for the post-crossover period (0.1% in the vaccine group and 0.05 in the placebo group); and cholecystitis (0.05% in the vaccine group and 0.01% in the placebo group). Non-cardiac, non-neurovascular embolic and thrombotic events were balanced; however, 8 participants in the vaccine arm experienced thrombotic/embolic events within 21 days of the most recent vaccine dose, without plausible alternative etiologies.

Serious Adverse Events

Serious adverse events were defined as any untoward medical occurrence that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, or resulted in persistent disability or incapacity. The proportions of participants who reported at least one serious adverse event were 1.0% in the vaccine group and 1.1% in the placebo group. The most common serious adverse events occurring at higher rates in the vaccine group than the placebo group were cerebrovascular accident (0.04% vs. 0%), cholecystitis acute (0.03% vs 0%), atrial fibrillation (0.04% vs. 0.02% placebo, pneumonia aspiration (0.02% vs. 0%), spontaneous abortion (0.02% vs. 0%). FDA judged one serious adverse event of angioedema as potentially related to vaccination. In evaluation of potential harms, cases of myocarditis or pericarditis were detected during Novavax COVID-19 clinical trials. Reports of myocarditis or pericarditis were also identified during postauthorization use of Novavax COVID-19 vaccine in countries outside the United States. Ongoing vaccine safety surveillance in the United States and international will help assess the possible risk for Novavax COVID-19 vaccine-associated myocarditis or pericarditis.

Data source: FDA briefing document