Supportive clinical safety data of vaccine using the Ad26 Vector

As of 04 September 2020, different Ad26 platform-based vaccines developed by Janssen have been administered to 114,174 participants. Safety data are available from six reports: AdVac safety database report V5.0 (4,874 participants enrolled as of the data cut-off date of 20 December 2019), additional reviews of individual case safety reports of SAEs and pregnancy exposures (up to 31 October 2020; cases which were not part of the current AdVac report), complete cumulative reviews of SAEs and pregnancy cases (up to the cut-off of 21 December 2020), and complete cumulative review of neuroinflammatory AEs (up to the cut-off of 21 January 2021).

Data from the AdVac safety database report V5.0 supported the accelerated development of the vaccine candidate Ad26.COV2.S for the prevention of COVID-19, including the dose levels used in the FIH.

Most of the data are from the Ebola programme. Significant amount of data is also available from the RSV and HIV programme. Data for other inserts are very limited. The majority of enrolled individuals were healthy, Black or African American, or White. Imbalance between groups observed in the AdVac safety database V5 (in particular, for region and ethnicity) should be explained and the impact on the results should be discussed (see list of recommendations).

Baseline seropositivity to Ad26 was evaluated in the three large Janssen Vaccines’ clinical vaccine programs (Ebola, HIV, and RSV) across various geographic locations and in varying study populations (n=3851). Ad26 seroprevalence varied by continent, with the highest seroprevalence reported in Africa (77.9% [95% CI 75.9;79.7],n=1,872), followed by Asia (41.4% [28.9;55], exclusively in Thailand, n=58), and comparatively low seroprevalence levels in North America (15.1% [13.5;16.9], exclusively USA, n=1,748), and Europe (11.6% [7.4;17.5], n=173). To assess the influence of natural pre-existing immunity to Ad26 on humoral responses, a cross-study analysis was performed by assessing insert-specific Ab specifically post 1 Ad26-based vaccination. Based on the limited data, it is considered that an impact of pre-existing anti-Ad26 vector immunity on insert specific vaccine-elicited immune responses cannot be excluded. The applicant has also presented the first data obtained in the COVID-19 program to further document this potential impact of immunity to Ad26. However, the data gathered so far do not allow the assessment of the impact of natural pre-existing anti-Ad26 vector immunity since only 2 subjects had Ad26 nAb at baseline. Of importance, the data of COVID-19 program so far do not indicate an apparent negative impact of anti-Ad26 vector immunity induced by the first vaccine dose on the insert specific vaccine-elicited humoral immune responses post-dose 2.

The impact on T cell responses was not presented. The potential impact of natural or vaccine induced pre-existing anti-Ad26 immunity on vaccine efficacy remains unclear and should be further

documented. Further data are expected with the COVID-19 program and would help to better

characterise the impact of natural and induced Ad26 immunity on the antigen specific vaccine-induced immune responses, and its possible impact on vaccine efficacy (see list of recommendations).

In healthy younger adults (18-60-year-old), overall, Ad26-based vaccines were well tolerated, irrespective of the insert, the dose level and the dose number; however, safety data have been provided irrespective of dose levels and per subject (cumulating AE after all doses). In next Advac reports, the applicant is recommended to provide the solicited AE separately for dose level 5x10¹⁰ (relevant for the COVID-19 vaccination) and other dose levels, and, separately, after dose 1 and after dose 2 (compared to placebo) (see list of recommendations).

Several factors could influence reactogenicity (age, region, pre-existing immunity to Ad26, antigen insert, and dose level). In particular, it has been observed that:

The frequencies (per subject) of local solicited AEs following Ad26 was slightly higher in the younger age category (64.0% of adults aged 18-30 years) compared to the 31-50 years and ≥50 years (56.5%

and 57.2% respectively). The frequencies of systemic solicited AEs following Ad26 was also higher in the younger age category (73.5% of adults aged 18-30 years) compared to the 31-50 years and ≥50 years (62.9% and 62.3% respectively).

The frequency of solicited AE local and systemic is generally much lower in West Africa than in other regions (East and Southern Africa, North America, Europe, and Asia), both for the active and placebo groups. Discrepancies across regions could also reflect differences in terms of pre-existing immunity to Ad26 (higher in Africa) and methodological differences between studies. This should be discussed in the next Advac report (see list of recommendations).

Overall, the frequency of solicited local (most notably injection site pain) and systemic AEs (mostly headache, fatigue, myalgia, and chills) tended to be lower in individuals with pre-existing Ad26 neutralising antibody titres (Ad26 VNA positivity at baseline) compared to individuals without pre-existing Ad26 neutralising antibody titres at baseline. This was observed for Zabdeno (EPAR) and confirmed by the cross-study analysis summarised in the report ‘Influence of Natural Pre-existing Immunity to Ad26 on Humoral Immune Responses post 1 Ad26-based Vaccination’ (Ebola and HIV programmes). The cross-study analysis indicated that the association remained when stratifying by continent. This observation is unlikely to impact the use of the vaccine. The independent effect of pre-existing immunity to the vector on reactogenicity remains not fully clear.

For the inserts that have been tested in more than 100 subjects, high differences of frequency of solicited local and systemic AE (all grade and severe – related to vaccine or not) have been reported depending on the insert. These differences are difficult to interpret given the confounding effect of study location (Africa vs other regions), age distribution, and dose level used. Hence, the independent effect of the insert on reactogenicity remains unclear. This should be discussed in a next Advac report, based on more detailed stratified analyses (see list of recommendations).

It is difficult to establish an effect of dose level, as relatively few individuals received Ad26 doses of 1×10⁹ vp, 1×10¹⁰ vp, and 9×10¹⁰ vp. When only groups with more than 100 individuals were considered (0.8×10¹⁰ vp, 2×10¹⁰ vp, 5×10¹⁰ vp, and 1×10¹¹ vp dose levels), there was a trend towards an increase in the frequency of some local solicited AEs (all grade and severe, in particular injection site pain), and solicited systemic AEs (all grade and severe, and considered related to study vaccine, in particular arthralgia, chills, fatigue, headache, myalgia, and nausea), following the increase in Ad26 dose. There was no clear trend in the frequency of unsolicited AEs with increasing the Ad26 dose.

An increased risk of HIV acquisition in individuals vaccinated with adenovirus-based vaccines is considered as an important potential risk. This safety concern has been raised with an Ad5-vectored HIV vaccine. An increased risk of HIV-1 acquisition was observed in subjects vaccinated with an experimental Ad5-vectored HIV vaccine compared to control subjects (Buchbinder et al., 2020). It was hypothesised that activated Ad5-specific CD4 T cells could increase rates of HIV-1 acquisition. Although the association between risk of HIV-1 acquisition and Ad5-based (or other Ad-based) vaccines is controversial and the mechanism for increased risk is unclear, this potential risk should be taken into account in studies with this viral vector platform. The overall assessment of the risk for increased HIV acquisition after vaccination with Ad26-based vaccines is considered to be theoretical. In the AdVac Safety Database V5.0, there were 3 cases of incident HIV infection in Ad26-vaccinated individuals in HIV-V-A004, all captured as SAEs from the same site, which is situated in a high endemic region for HIV infection (all cases presenting risk factors for HIV infection) (compared to none in the placebo group). In study VAC52150EBL2002 (Ebola vaccine), one adult male participant tested HIV

seropositive approximately 1 year after receipt of one dose of Ad26.ZEBOV (sexually inactive at study enrolment; no further information available about risk factors for HIV infection). There have been no HIV infections reported in the development programs of RSV, Filovirus, and malaria Ad26-vectored

vaccines. To date, there were no incident HIV infections reported in clinical studies with Ad26.COV2.S.

The next version of the Adenoviral Vaccine Safety Database (V6.0) should be submitted including a discussion of the potential increased risk of HIV acquisition in individuals vaccinated with adenovirus-based vaccines with a review of reported cases in the updated Ad26 platform data (expected for approximatively April 2021). (see list of recommendations)

Adults aged ≥60 years have been included in a Phase 1 and a Phase 2a study of the RSV vaccine clinical development program. In total, 228 individuals aged ≥60 years received an Ad26.RSV.preF based regimen in these studies. Overall, no safety concerns have been raised to date in this

population. However, data are very limited, and only brief conclusions have been given for adults ≥60 years. In next Advac reports, the applicant should provide more detailed data by age group (less than 65, between 65-74, 75-84 and 85 and above) and to discuss them (see list of recommendations).

In the Ad26 platform safety data, 1,631 pregnancy cases were reported (majority reported in Ebola vaccine trials in DRC and Rwanda) and 939 final pregnancy outcomes were reported: healthy baby for 781, various other outcomes for 158 pregnancies (including 102 spontaneous abortions), ongoing for 243, and unknown/not reported for 449. Of these 1,631 pregnancies, caesarean section delivery was reported as delivery method in 193 pregnancies and 61 reported normal delivery. Overall, pregnancy outcomes are consistent with what could be expected in sub-Saharan Africa.

For most pregnancies, vaccine exposure took place within 3 months preceding conception (N=464).

The number of pregnancy cases is similar for exposure during the first (N=280), second (N=242) or third trimester (N=267) of pregnancy. For 378 cases, time of vaccine exposure was not reported. The number of pregnancies exposed in the first trimester (280) is lower than the threshold of at least 300 pregnancies exposed to reach a conclusion on the effect on malformation ("Guideline on risk

assessment of medicinal products on human reproduction and lactation: from data to labelling"

EMEA/CHMP/203927/2005).

Moreover, although, overall, the cumulative review of pregnancies is promising, a comparison with the frequency of outcomes in pregnancies that were not exposed to Zabdeno is missing to interpret the data adequately.

The majority of the reported solicited AE were of low or mild intensity and lasted for few days after administration of the vaccine. No significant safety issues have been identified to date.

Overall, the Janssen Ad26-based vaccines have an acceptable safety profile in all populations studied, including young adults, children and adolescents, ≥60-year-old, HIV-infected individuals, pregnant women and individuals with pre-existing Ad26 neutralising antibodies. The numbers of children and adolescents, and individuals ≥60-year-old in the safety database is however limited, as well as the number of HIV-infected individuals.

Safety data of Ad26-based vaccine in (older) adults with comorbidities, which are relevant for the COVID-19 vaccine, are lacking. Moreover, it is noted that only about 10% of all subjects in the AdVac safety database were European, and about one third were White.

The absence of safety concern may be considered reassuring in terms of the safety of the

Ad26.COV2.S vaccine and other future Ad26 based vaccines. However, safety and reactogenicity may be driven by both the platform and the insert. It is noted that differences in the frequency of solicited AEs were reported across inserts, although the independent effect of the insert on reactogenicity and safety is currently unclear (given the confounding effect of factors such as dose level used, age,

region, and pre-existing immunity to the vector). Overall, it remains unclear to which extend the safety profile of Ad26 vaccines can be extrapolated from one insert to another.