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. 2022 Jul:81:104128.
doi: 10.1016/j.ebiom.2022.104128. Epub 2022 Jun 30.

An exploratory analysis of the response to ChAdOx1 nCoV-19 (AZD1222) vaccine in males and females

Natalie Gabrielle Marchevsky  1 , Grace Li  2 , Parvinder Aley  1 , Sue Ann Costa Clemens  3 , Jordan Richard Barrett  4 , Sandra Belij-Rammerstorfer  4 , Sagida Bibi  1 , Elizabeth Clutterbuck  1 , Christina Dold  1 , Sally Felle  1 , Amy Flaxman  4 , Pedro Folegatti  4 , Daniel Jenkin  4 , Sarah Gilbert  4 , Sarah Kelly  1 , Teresa Lambe  5 , Emma Plested  1 , Maheshi Ramasamy  1 , Nisha Singh  1 , Holly Smith  4 , Stephen Taylor  6 , Lily Weckx  7 , Andrew John Pollard  8 , Merryn Voysey  8 ; Oxford COVID Vaccine Trial Group
Affiliations

An exploratory analysis of the response to ChAdOx1 nCoV-19 (AZD1222) vaccine in males and females

Natalie Gabrielle Marchevsky et al. EBioMedicine. 2022 Jul.

Abstract

Background: There are known differences in vaccine reactogenicity and immunogenicity by sex. Females have been shown to report greater reactogenicity and generate higher humoral and cellular immune responses than males following vaccination with several different vaccines. Whether this is also the case for COVID-19 vaccines is currently unknown, as COVID-19 vaccine study data disaggregated by sex are not routinely reported. Therefore, we have assessed the influence of sex on reactogenicity, immunogenicity and efficacy of COVID-19 vaccine ChAdOx1 nCoV-19.

Methods: Vaccine efficacy was assessed in 15169 volunteers enrolled into single-blind randomised controlled trials of ChAdOx1 nCoV-19 in Brazil and the UK, with the primary endpoint defined as nucleic acid amplification test (NAAT)-positive symptomatic SARS-CoV-2 infection. All participants were electronically randomised to receive two standard doses of vaccine or the control product. Logistic regression models were fitted to explore the effect of age and sex on reactogenicity, and linear models fitted to log-transformed values for immunogenicity data. Reactogenicity data were taken from self-reported diaries of 788 trial participants. Pseudovirus neutralisation assay data were available from 748 participants and anti-SARS-CoV-2 spike IgG assay data from 1543 participants.

Findings: 7619 participants received ChAdOx1 nCoV-19 and 7550 received the control. Vaccine efficacy in participants after two doses of ChAdOx1 nCoV-19 (4243 females and 3376 males) was 66.1% (95% CI 55.9-73.9%) in males and 59.9% (95% CI 49.8-67.9%) in females; with no evidence of a difference in efficacy between the sexes (vaccine by sex interaction term P=0.3359). A small, statistically significant difference in anti-spike IgG was observed (adjusted GMR 1.14; 95% CI 1.04-1.26), with higher titres in females than males, but there were no statistically significant differences in other immunological endpoints. Whilst the majority of individuals reported at least one systemic reaction following a first dose of ChAdOx1 nCoV-19, females were twice as likely as males to report any systemic reaction after a first dose (OR 1.95; 95% CI 1.37-2.77). Measured fever of 38°C or above was reported in 5% of females and 1% of males following first doses. Headache and fatigue were the most commonly reported reactions in both sexes.

Interpretation: Our results show that there is no evidence of difference in efficacy of the COVID-19 vaccine ChAdOx1 nCoV-19 in males and females. Greater reactogenicity in females was not associated with any difference in vaccine efficacy.

Funding: Studies were registered with ISRCTN 90906759 (COV002) and ISRCTN 89951424 (COV003) and follow-up is ongoing. Funding was received from the UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil, and AstraZeneca.

Keywords: COVID-19; Clinical trials; Sex-differences; Vaccination.

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Conflict of interest statement

Declaration of interests Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. AstraZeneca reviewed the final manuscript before submission, but the authors retained editorial control. SCG is a cofounder of and shareholder in Vaccitech (collaborators in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and was a consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care's JCVI, but does not participate in policy advice on coronavirus vaccines, and was a member of the WHO Strategic Advisory Group of Experts (SAGE) until 2022. MNR has acted as PI on commercial vaccine trials sponsored by Astra Zeneca and VBI vaccines but not personally received payment for this work. MV has received grants from the NIHR and Bill and Melinda Gates Foundation not related to this work and participated on Data Safety Monitoring Boards for NIHR funded projects not related to this paper.

Figures

Figure 1
Figure 1
CONSORT diagram for the efficacy cohort. Chart shows numbers of participants enrolled and vaccinated in the COV002 (UK) study and the COV003 (Brazil) study. Shown are numbers who received each vaccine within each trial and reasons for exclusion from the efficacy analysis for each group.
Figure 2
Figure 2
Immune response 28 days after a second dose of ChAdOx1 nCoV-19 in females and males and females. Boxplots represent the median and 25th and 75th percentiles; each data point is one participant. The number of participants included in each group is shown beneath each box plot. Summary statistics and further analysis of these data are provided in Table S7. a) Anti-SARS-CoV-2 spike IgG by multiplex immunoassay. P=0.0054 from linear model of log-transformed antibody values adjusting for country, age, health/social care worker, ethnicity, and interaction between age and health/social care worker. AU/mL: Arbitrary Units per millilitre; b) Neutralisation titres by pseudovirus assay. P=0.2795 from linear model of log-transformed antibody values adjusting for country, age, health/social care worker, ethnicity, and interaction between age and health/social care worker. IC50: concentration achieving 50% inhibition of viral replication.
Figure 3
Figure 3
Anti-spike antibody isotypes, subclasses and function in males and females at day 28 after dose 2. ADCD: antibody dependent complement deposition; ADMP: antibody dependent monocyte phagocytosis; ADNKA: antibody dependent natural killer cell activation; ADNP: antibody dependent neutrophil phagocytosis. EU: Elisa Units; OD: optical density; Ig: Immunoglobulin. Comparisons of normalized data between males (M) and females (F) by Wilcoxon rank sum tests: all Bonferroni-adjusted P-values all >0.05. Boxplots represent the median and 25th and 75th percentiles; each data point is one participant. The number of participants included in each analysis is shown beneath each box plot. Numbers of samples were limited by the experimental size of the assays and laboratory capacity. Summary Statistics provided in Table S8.
Figure 4
Figure 4
Solicited systemic reactions after a first dose of ChAdOx1 nCoV-19 in participants returning diary data, by sex and age at vaccination. The numbers of female and male participants included in each age group are shown on the final reaction panel (nausea). These numbers apply for all solicited symptoms presented in this figure except where indicated with *, where the denominator is n=5 fewer participants for the fever panel due to missing temperature readings. Data presented are maximum symptom severity reported over the first 0-7 days following a first dose of ChAdOx1 nCoV-19. Participants categorised the severity of their reactions using pre-specified criteria (Table S1). F: females; M: males.
Figure 5
Figure 5
Solicited local reactions after a first dose of ChAdOx1 nCoV-19 in participants returning diary data, by sex and age at vaccination. The numbers of female and male participants included in each age group are shown on the final reaction panel (induration). These numbers apply for all solicited symptoms presented in this figure. Data presented are maximum severity reported over the first 0-7 days following a first dose of ChAdOx1 nCoV-19. Participants categorised the severity of their reactions using pre-specified criteria (Table S1). F: females; M: males.
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