Neutrophil Counts in Healthy South African Infants: Implications for Enrollment and Adverse Event Grading in Clinical Trials in an African Setting

Koen, Anthonet; Jose, Lisa; Madhi, Shabir А.; Fix, Alan; Cryz, Stanley; Groome, Michelle

doi:10.1016/j.ympdx.2019.100005

Cited by 2 publications

(2 citation statements)

References 14 publications

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“…Abnormalities in hematological parameters, including ANC, are used to evaluate the eligibility of volunteers to participate in clinical trials and to assess any emerging safety signals during the conduct of the trial. Misclassification of ANC values may affect enrollment and might also lead to incorrect interpretation of the safety profile of a pharmaceutical product [ 19 ]. During the conduct of the S. sonnei 1790GAHB vaccine studies, transient and clinically asymptomatic neutropenia events have been observed.…”

Section: Discussionmentioning

confidence: 99%

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

Ryck¹,

Sarakinou

Nakakana

et al. 2022

Infect Dis Ther

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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. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-022-00596-x.

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Section: Discussionmentioning

confidence: 99%

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

Ryck¹,

Sarakinou

Nakakana

et al. 2022

Infect Dis Ther

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“…Reference ranges previously obtained from non-African populations may, therefore, have limited applicability to populations of African ethnicity in clinical practice or research [ 9 , 10 ]. A previous study demonstrated that an additional 16% of potentially eligible, healthy participants were excluded from participation in a rotavirus vaccine clinical trial on the basis of neutropenia because reference ranges inappropriate for the study population were used in their assessment [ 11 ]. The use of inappropriate reference ranges in clinical trials to determine participant eligibility may result in the underrepresentation of this population in research.…”

Section: Introductionmentioning

confidence: 99%

Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial

et al. 2021

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Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007–2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20–26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21–30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625–2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265–2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126–4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3–20.1) vs. 16.5 (95% CI: 14.6–18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3–29.2) vs. 14.8 (95% CI: 13.0–16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.

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Neutrophil Counts in Healthy South African Infants: Implications for Enrollment and Adverse Event Grading in Clinical Trials in an African Setting

Cited by 2 publications

References 14 publications

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

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

Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial

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