Safety in special populations

The safety parameters were reviewed by subgroup for age at randomisation, comorbidity at baseline, by Region, by gender, baseline serostatus and HIV infection. Overall, the safety profile of Ad26 5x1010 was generally similar independently of the subgroups, in particular the frequencies of subjects with SAEs, MAAEs and AESIs (rare). In the Ad26 5x1010 group, for all subgroups, most solicited AEs were Grade 1 or Grade 2 in severity, and most solicited AEs were transient in nature and reported as resolved. The nature of the local and systemic AEs recorded was similar, showing the same pattern as for the pooled population.

2.6.7.1. Age groups

Main clinical study: VAC31518COV3001

Overall, the demographic and baseline characteristics were consistent between these age subgroups.

However, not surprisingly, in the Ad26 5x10¹⁰ group (safety subset), there were less comorbidities at baseline in the younger group (31% for subjects 18 to 64 years of age), compared to the older group (45% for subjects ≥65 years of age).

In the Ad26 5x10¹⁰ group the frequency of subjects with solicited local AEs clearly decreases with age 55.7% for subjects aged ≥18 to 64 vs. 31.8% for subjects aged ≥65 years. This lower frequency in participants aged ≥65 years was reported for all selected solicited local AEs, including the most frequent solicited local AE, ie, vaccination site pain: 54.3% in subjects aged ≥18 to 64 (86% grade 1, 13.4% grade 2, 0.6% grade 3) vs. 29.6% in subjects aged ≥65 years (94.3% grade 1, 4.4% grade 2, 1.3% grade 3).

The frequency of subjects with solicited systemic AEs also clearly decreases with age: 59.6% for subjects aged ≥18 to 64 vs. 40.2% for subjects aged ≥65 years. A higher frequency was reported for all selected solicited systemic AEs (fatigue, headache, myalgia, nausea, and pyrexia) in younger subjects. In particular, there were 11% subjects aged ≥18 to 64 years with pyrexia compared to 2.4% subjects aged

≥65 years.

In the Ad26 5x10¹⁰ group, for all the 2 age subgroups, most solicited AEs were Grade 1 or Grade 2 in severity. There were slightly more grade 1 solicited local and systemics AEs in subjects aged ≥65 years compared to subjects aged ≥18 to 64, and less grade 2 solicited local and systemics AEs.

Table 35 Adverse Events (MedDRA Terms) for Elderly Participants (Study VAC31518COV3001)

- Disability/incapacity FAS/ Entire

Study 1

(<0.1%)  1 (<0.1%) 0 1 (0.5%) 7

(<0.1%) 1

(<0.1%) 1 (0.1%) 0 - Other (medically

significant): MAAE FAS/ Entire

Study 207

Psychiatric disorders Safety Subset /

Cardiac disorders Safety Subset / Post Dose

 0  1 (0.1%)  1 (0.3%)   0 1

(<0.1%) 0 0 0

Vascular disorders Safety Subset /

Infections and

infestations Safety Subset / Post Dose

(2.1%)  42  10 (1.1%)  4 (1.1%)  1 (2.5%) 60 (2.9%) 16 (1.7%) 9 (2.7%) 2 (5.3%)

Anticholinergic

syndrome: broad SMQ Safety Subset / Post Dose

18 (0.9%) 5 (0.5%) 1 (0.3%) 0 9 (0.4%) 5 (0.5%) 2 (0.6%) 0

Sum of postural hypotension, falls, black outs, syncope, dizziness, ataxia

Safety Subset / Post Dose

(0.7%)  14  6 (0.7%) 1 (0.3%)  0 10 (0.5%) 6 (0.6%) 2 (0.6%) 1 (2.6%)

AE = adverse event; FAS = Full Analysis Set; MAAE = medically-attended adverse event; MedDRA = Medical Dictionary for Regulatory Activities; SMQ = standardised MedDRA query; y = years;

2.6.7.2. Co-morbidities

In the safety subset of main trial COV3001, the frequencies of subjects with local and systemic solicited AEs decrease for subjects with baseline comorbidities compared to subjects without baseline comorbidities in the Ad26.COV2.S group only (differences not observed in the placebo group):

- The frequency of solicited local AEs was lower in participants with one or more comorbidities (42.9%) compared to participants without comorbidities at baseline (54%).

- Solicited systemic AEs were reported less frequently in participants with one or more comorbidities (49.6%) compared to participants without comorbidities at baseline (58.1%).

Subjects 18-64 years of age with comorbidities at baseline shows less local solicited AEs than the subjects 18-64 years of age without comorbidities, and less systemic solicited AEs than the subjects 18-64 years of age without comorbidities. Subjects from 65 years of age with comorbidities at baseline shows similar reactogenicity than the subjects from 65 years of age without comorbidities.

No specific concerns arise in the observed safety profile so far.

2.6.7.3. Use in pregnancy and lactation

Up to the cut-off date of 31 December 2020, 8 pregnancies were reported in the GMS database for study COV3001: 4 in COVID-19 vaccine group and 4 in placebo group. In the COVID-19 group, 2 pregnancies were still ongoing, and there were 1 spontaneous abortion and 1 ectopic pregnancy (both assessed as not related to vaccine). In the placebo group, 1 pregnancy was still ongoing, and there were 1 incomplete abortion and 2 elective abortions. Although, up to the cut-off date of 31 December 2020, 285 breastfeeding women (128 in Ad26.COV2.S group and 157 in placebo group) were enrolled, no further information regarding breastfeeding was requested during the study.

Use during pregnancy and in breastfeeding women are considered as missing information in the RMP.

2.6.7.4. By Region

In the safety subset of the main trial COV3001, the frequencies of subjects with local and systemic solicited AEs were slightly higher in Northern America compared to Latin America and Southern Africa in the Ad26.COV2.S group only (differences not observed in the placebo group).

2.6.7.5. By gender

In the Ad26

5x10

¹⁰ group (FAS) regarding the main trial COV3001, there were 12,071 males (55.1%) and 9,820 females (44.9%).

In the safety subset, the frequencies of subjects with local and systemic solicited AEs were higher in females compared to males in the Ad26.COV2.S group only (differences not observed in the placebo group):

- In the Ad26.COV2.S group, the frequency of local solicited AEs was higher in female (54.5%) compared to males (46.2%).

- In the Ad26.COV2.S group, the frequency of systemic solicited AEs was also higher in female (59.9%) compared to males (50.7%)

No major differences are observed for the grade 3 local solicited events (1% in females vs. 0.4% in males).

2.6.7.6. By baseline Serostatus

In the Ad26

5x10

¹⁰ group (FAS) regarding main trial COV3001, there were 2,151 subjects (9.8%) seropositive at baseline and 19,744 subjects (90.2%) seronegative at baseline (respectively, 2,066 subjects (9.4%) and 19,822 subjects (90.6%) in placebo group). Overall, the safety profile of Ad26

5x10

¹⁰ was generally similar in adults seropositive and seronegative at baseline for SARS-CoV-2. The nature of the local and systemic AEs recorded was similar, showing the same pattern as for the pooled population, without any clinically meaningful differences in frequencies. However, the number of vaccinated subjects who were seropositive at baseline is too limited in the safety subset to draw any definitive conclusions.

No specific concerns arise in the observed safety profile so far.

2.6.7.7. By HIV infection

In the main trial: COV3001, there were 601 subjects (2.7%) HIV infected at baseline and 8,335 subjects (38.1%) not HIV infected at baseline vaccinated with Ade26.COV2.S. No safety concern was observed in adults with stable/well-controlled HIV infection who received the COVID-19 Vaccine Janssen

Nevertheless, the number of vaccinated subjects HIV infected at baseline is too limited in the safety subset to draw any conclusions

regarding reactogenicity

(34 in Ad26.COV2.S group and 25 in placebo group). Use in immunocompromised patients is identified as a missing information in the RMP.

2.6.7.8. By dose level

Supportive Clinical Studies (COV1001, COV1002, COV2001)

Safety data from Ad26.COV2.S administered at different dose levels are available from COV1001 (5x10¹⁰ vp and 1x10¹¹ vp) and COV2001 (1.25x10¹⁰ vp, 2.5x10¹⁰ vp, 5x10¹⁰ vp, and 1x10¹¹ vp) in adults ≥18 to ≤55 years and ≥65 years of age and from COV1002 (5x10¹⁰ vp and 1x10¹¹ vp) in adults

≥20 to ≤55 years of age. Safety data up to 28 days post dose 1 for each study are described below.

For COV1001 and COV2001, data post dose 1 were pooled within each cohort by dose level within each study.

Overall, no safety concerns were identified after vaccination with Ad26.COV2.S at dose levels up to 1x10¹¹ vp. The available safety data are supportive of the dose selection for the Phase 3 studies.

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