GMMA Technology for the Development of Safe Vaccines: Meta-Analysis of Individual Patient Data to Assess the Safety Profile of Shigella sonnei 1790GAHB Vaccine in Healthy Adults, with Special Focus on Neutropenia

Abstract

Introduction: Shigellosis is a major health concern among children < 5 years of age from developing countries, and there are no widely available vaccines to prevent it. The GMMA-based 1790GAHB investigational vaccine against Shigella sonnei was well tolerated and immunogenic in phase 1 and 2 studies conducted in healthy adults from Shigella endemic and non-endemic populations. Based on pooled data of five individual trials, we assessed the association between vaccine administration and the risk of neutropenia as well as the overall safety profile of 1790GAHB.

Methods: The risk ratio (RR) of neutropenia was evaluated between participants receiving 1790GAHB (vaccinees) and active comparator/placebo (controls) using different ethnicity-specific absolute neutrophil count (ANC) thresholds established to define neutropenia. Safety was assessed in terms of solicited, unsolicited, and serious adverse events (AEs).

Results: Of the 279 participants, 11 (5.5%) vaccinees and 4 (5.0%) controls had ANC below the appropriate threshold within 7 days post-vaccination. RR was 0.96 [95% confidence interval (CI) 0.54-1.70]. When neutrophil counts of participants of African descent were measured against an ethnicity non-specific threshold, they resulted in neutropenia episodes in 30 (37.0%) vaccinees and 16 (30.2%) controls, while only 2 (2.5%) vaccinees and 1 (1.9%) control had neutropenia when the ethnicity-specific threshold was applied. RRs were 0.98 (95% CI 0.75-1.28) and 1.30 (95% CI 0.1-17.6), respectively. Solicited and unsolicited AEs were slightly more frequent among vaccinees than controls. No serious AEs, other than neutropenia cases, were recorded in the vaccine group.

Conclusion: By applying the appropriate threshold, no increased risk of neutropenia was identified in vaccinees compared with the controls. The frequency of neutropenia events varied drastically when ethnicity-appropriate thresholds were applied. This observation highlights the importance of selecting appropriate cut-off values according to the correct population reference. Overall, the 1790GAHB vaccine demonstrated an acceptable safety profile.

Keywords: 1790GAHB vaccine; GMMA technology; Neutropenia; Safety profile; Shigella sonnei.

Fig. 1

Study design and participants of clinical trials with the S. sonnei 1790GAHB candidate vaccine included in the current analysis (exposed set). OAg O-Antigen. Population set for each analysis was defined according to the evaluated endpoints: neutropenia events were analyzed in the neutropenia safety set, solicited/unsolicited adverse events were analyzed in the solicited/unsolicited safety set, and serious adverse events were analyzed in the exposed set. 1790GAHB study vaccine was administered by intramuscular route. ^aParticipants were randomized to receive the study vaccine by intradermal, intranasal, or intramuscular route

Fig. 2

Percentage of participants with ANC below the DAIDS threshold for Black/African American and the FDA threshold for other than Black/African American participants (a) and geometric mean (b) and geometric mean ratio (c) of ANC within 7 days after each dose and overall (neutropenia safety set). ANC absolute neutrophil count, RR risk ratio, DAIDS Division of Acquired Immunodeficiency Syndrome, FDA US Food and Drug Administration. ^aUpper limit is 26.5. Error bars represent 95% confidence intervals. The area of the orange circles is proportional to the values of risk ratios/between-group ratios

Fig. 3

Percentage of Black/African American participants with ANC below the FDA (a) and DAIDS (b) thresholds and geometric mean (c) and geometric mean ratio (d) of ANC within 7 days after each dose and overall (neutropenia safety set). ANC absolute neutrophil count, RR risk ratio, DAIDS Division of Acquired Immunodeficiency Syndrome, FDA US Food and Drug Administration. *Upper limit is 97.5. **Upper limits are 52.2 (1790GAHB group) and 97.5 (control group). ^#Upper limits are > 999.9 in both groups. ^§Upper limits are 17.1 (1790GAHB group) and 6.7 (control group). The area of the orange circles is proportional to the values of risk ratios/between-group ratios

Fig. 4

Percentage of Black/African American participants with neutropenia as defined by DAIDS and FDA, within 7 days after each dose and overall (neutropenia safety set). DAIDS Division of Acquired Immunodeficiency Syndrome, FDA US Food and Drug Administration, RR risk ratio of vaccinated participants reporting neutropenia at least once against participants receiving control. The area of the orange circles is proportional to the values of risk ratios/between-group ratios

Fig. 5

Summary of solicited adverse events reported within 7 days after each dose and overall (solicited safety set). AE adverse event, RR risk ratio. Solicited AEs collected in the studies were pain, erythema, induration, swelling, facial edema, nasal pain, rhinorrhea (local), and arthralgia, chills, fatigue, headache, malaise, myalgia, and fever (systemic). The area of the orange circles is proportional to the values of risk ratios/between-group ratios