Harmonizing the collection of solicited adverse events in prophylactic vaccine clinical trials

Figures & data

Figure 1. Incidences and severity of solicited systemic or local AEs within 7 days following each of the 2 doses of either placebo or the Moderna COVID-19 vaccine.

Table 1. Incidences of solicited systemic adverse events within 7 days following vaccination with the recombinant zoster vaccine (RZV) or placebo.

		RZV N=4372		Placebo N=4375
Symptom	Type	n (%)	95% CI	n (%)	95% CI
Fatigue	Any severity	2006 (45.9)	(44.4–47.4)	728 (16.6)	(15.5–17.8)
	Grade 3	241 (5.5)	(4.9–6.2)	46 (1.1)	(0.8–1.4)
	Medical visit	31 (0.7)	(0.5–1.0)	18 (0.4)	(0.2–0.6)
Gastrointestinal symptoms	Any severity	787 (18)	(16.9–19.2)	386 (8.8)	(8–9.7)
	Grade 3	61 (1.4)	(1.1–1.8)	25 (0.6)	(0.4–0.8)
	Medical visit	28 (0.6)	(0.4–0.9)	13 (0.3)	(0.2–0.5)
Headache	Any severity	1714 (39.2)	(37.8–40.7)	700 (16)	(14.9–17.1)
	Grade 3	157 (3.6)	(3.1–4.2)	30 (0.7)	(0.5–1)
	Medical visit	35 (0.8)	(0.6–1.1)	12 (0.3)	(0.1–0.5)
Myalgia	Any severity	2023 (46.3)	(44.8–47.8)	529 (12.1)	(11.1–13.1)
	Grade 3	236 (5.4)	(4.7–6.1)	31 (0.7)	(0.5–1)
	Medical visit	36 (0.8)	(0.6–1.1)	16 (0.4)	(0.2–0.6)
Shivering	Any severity	1232 (28.2)	(26.8–29.5)	259 (5.9)	(5.2–6.7)
	Grade 3	192 (4.4)	(3.8–5)	11 (0.3)	(0.1–0.4)
	Medical visit	19 (0.4)	(0.3–0.7)	8 (0.2)	(0.1–0.4)
Temperature (oral)	≥38°C	940 (21.5)	(20.3–22.7)	132 (3)	(2.5–3.6)
	>39°C	14 (0.3)	(0.2–0.5)	6 (0.1)	(0.1–0.3)
	Medical visit	24 (0.5)	(0.4–0.8)	9 (0.2)	(0.1–0.4)

°C, degree Celsius; CI, confidence interval;

N = number of vaccinated participants who were enrolled in the cohort for which solicited AEs were collected

n/% = number/percentage of participants reporting the solicited AE within 7 days post vaccination (ie from the day of vaccination up day 6 post-vaccination)

Grade 3 =solicited AE who prevented normal daily activity

Medical visit = solicited AE leading to medical attention (defined as unscheduled visit to or from medical personnel for any reason, including emergency room visits)

Table 2. Incidences of solicited and unsolicited systemic adverse events within 7 days of the recombinant zoster vaccine (RZV) or placebo.

			RZV		Placebo
Symptom	Type	Cohort	(%)	95% CI	(%)	95% CI
Fatigue	Any grade	Solicited	45.9	(44.4–47.4)	16.6	(15.5–17.8)
	Grade 3	Solicited	5.5	(4.9–6.2)	1.1	(0.8–1.4)
	PT	Unsolicited	6.1	(5.3–7.0)	1.0	(0.7–1.5)
Gastrointestinal symptoms	Any grade	Solicited	18.0	(16.9–19.2)	8.8	(8.0–9.7)
	Grade 3	Solicited	1.4	(1.1–1.8)	0.6	(0.4–0.8)
	HLT	Unsolicited	3.3	(2.7–4.0)	1.2	(0.9–1.7)
Headache	Any grade	Solicited	39.2	(37.8–40.7)	16.0	(14.9–17.1)
	Grade 3	Solicited	3.2	(2.7–3.7)	0.7	(0.5–1.0)
	PT	Unsolicited	12.3	(11.1–13.4)	3.4	(2.8–4.1)
Myalgia	Any grade	Solicited	46.3	(44.8–47.8)	21.1	(11.1–13.1)
	Grade 3	Solicited	5.4	(4.7–6.1)	0.7	(0.5–1.0)
	PT	Unsolicited	7.4	(6.5–8.4)	0.6	(0.4–1.0)
Shivering	Any grade	Solicited	28.2	(26.8–29.5)	5.9	(5.2–6.7)
	Grade 3	Solicited	4.4	(3.8–5.0)	0.3	(0.1–0.4)
Chills	PT	Unsolicited	7.0	(6.2–8.0)	0.3	(0.2–0.6)
Fever	≥38°C	Solicited	21.5	(20.3–22.7)	3.0	(2.5–3.6)
	>39°C	Solicited	0.3	(0.2–0.5)	0.1	(0.1–0.3)
Pyrexia	PT	Unsolicited	16.8	(15.5–18.1)	0.4	(0.2–0.7)

°C, degree Celsius; CI, confidence interval; HLT, High-level term; PT, preferred term;

HLT/PT were used to derive the % for unsolicited AE similar to solicited AE,

*%, percentage of participants reporting the symptom at least once

Cohort with solicited events: RZV-group: N=4,372; Control group: N=4,375; Cohort with only unsolicited events: RZV-group: N=3,238; Control group: N=3,246)

% = percentage of participants reporting the AE within 7 days post vaccination (i.e. from the day of vaccination up day 6 post-vaccination)

Grade 3 = AE who prevented normal daily activity

Table 3. Estimating adverse event (AE) incidence after co-administration vs incidence after single administration of each vaccine, in the absence of enhancement due to co-administration.

Adverse event	Co-administration vaccine A and B	Single administration of vaccine A	Single administration of vaccine B	Estimate without interaction
Fatigue	45.4%	20.2%	29.5%	43.7%
Swelling	21.3%	6.3%	7.1%	13.0%

*computed as 1 - the product of (1-incidence) for each separately administered vaccine: for fatigue: 1-[(1-0.202)×(1-0.295)]=0.4374=43.7%; for shivering: 1-[(1-0.063)×(1-0.071)]=0.1295=13.0%

%: percentage of participants reporting the solicited AE at least once

Figure 2. Upper limit of the one-sided 95% CI of the true incidence of an event according to the number of participants in the absence of reported cases.

Figure 3. Width of the two-sided 95% confidence interval of the true incidence of an event according to the number of participants and for different observed incidences.

Table 4. Steps to consider during study design, analysis and when updating the label with AE data.

Step	Details
During study design	Identify the AEs to be solicited based on the mode of action and biological plausibility for a causal association with the vaccine and intended target population (refer to Section 2.2 and 3.1).
	Determine the intended study collection and reporting procedures – i.e. the use of electronic vs paper diaries, collection of AEs of special interest, identify procedures to limit missing data, and procedures for data reconciliation (refer to Section 3.2).
	Consider the use of distinct safety data collection sub-cohorts for (1) reactogenicity (i.e. daily recording of solicited AEs by subjects) and (2) unsolicited AEs (including AESIs, SAEs) (visits scheduled for collection of unsolicited AEs by study staff). Identify the sample size needed for the required degree of precision (refer to Section 3.7).
	Define severity grading of AEs as per recommended guidance or prepare a justification for deviating from the guidance. Ensure standardization within the project.
	For co-administration studies, ensure the comparison addresses the question on co-administration vs sequential administration, as opposed to addressing co-administered vs a single vaccine only (refer to Section 3.6).
Preparing the study report and updating the prescribing information	Present incidence rates head-to-head with a control group and analyze data from the solicited AEs cohort separately from the unsolicited AEs safety cohort. Present summaries per severity grading, seriousness and if medical attention/medical visit was required.
Updating the prescribing information	Consider grouping clinically similar AE terms in the prescribing information (refer to Section 4.2).