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

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.

The effect of H1N1 vaccination on serum miRNA expression in children: A tale of caution for microRNA microarray studies.

BACKGROUND: MicroRNAs (miRNAs) are a class of small regulatory RNAs around 21-25 nucleotides in length which govern many aspects of immunity including the host innate and adaptive responses to infection. RT-qPCR studies of select microRNAs show that vaccination alters the expression circulating microRNAs but the effect of vaccination on the global microRNA population (i.e. micronome) has never been studied. AIM: To describe vaccine associated changes in the expression of microRNAs 21 days after vaccination in children receiving a pandemic influenza (H1N1) vaccination. METHOD: Serum samples were obtained from children aged 6 months to 12 years enrolled in an open label randomised control trial of two pandemic influenza (H1N1) vaccines, in which participants received either ASO3B adjuvanted split virion or a whole virion non-adjuvanted vaccine. MicroRNA expression was profiled in a discovery cohort of participants prior to, and 21 days after vaccination using an Agilent microarray platform. Findings were followed up by RT-qPCR in the original discovery cohort and then in a validation cohort of participants taken from the same study. RESULTS: 44 samples from 22 children were assayed in a discovery cohort. The microarray results revealed 19 microRNAs were differentially expressed after vaccination after adjustment for multiple testing. The microarray detected ubiquitous expression of several microRNAs which could not be validated by RT-qPCR, many of which have little evidence of existence in publicly available RNA sequencing data. Real time PCR (RT-qPCR) confirmed downregulation of miR-142-3p in the discovery cohort. These findings were not replicated in the subsequent validation cohort (n = 22). CONCLUSION: This study is the first study to profile microRNA expression after vaccination. An important feature of this study is many of the differentially expressed microRNAs could not be detected and validated by RT-qPCR. This study highlights the care that should be taken when interpreting omics biomarker discovery, highlighting the need for supplementary methods to validate microRNA microarray findings, and emphasises the importance of validation cohorts. Data from similar studies which do not meet these requirements should be interpreted with caution.

Evaluation of haemophilus influenzae type b vaccine for routine immunization in Nepali infants.

BACKGROUND: Haemophilus influenzae type b (Hib) carriage and disease studies in Nepali children suggest a significant burden of infection. Hib conjugate vaccines (HibCV) do not have uniform immunogenicity between populations. We determined the immunogenicity of HibCV in Nepali infants, before its introduction into the routine immunization schedule. METHODS: Ninety infants recruited at Patan Hospital, Kathmandu, received 3 doses of the HibCV with routine immunizations (diphtheria, tetanus, whole cell pertussis-hepatitis B vaccine + oral polio vaccine) at 6, 10 and 14 weeks of age, and a HibCV booster at 52 weeks. Anti-polyribosylribitol phosphate (PRP) concentrations were measured at 18, 52 and 56 weeks, and the antibody persistence at 52 weeks was compared with antibody values in unimmunized controls (n = 30). RESULTS: After 3 doses of primary immunizations, at 18 weeks of age (n = 74), all infants had anti-PRP concentrations above the accepted thresholds for short- and long-term protection (0.15 and 1.0 µg/mL, respectively). At 1 year of age, before administration of the booster of HibCV, the anti-PRP geometric mean antibody concentration was 2.76 µg/mL (confidence interval: 1.88-4.07) in sera from the immunized children compared with 0.11 µg/mL (95% confidence interval: 0.08-0.17) in the nonimmunized control group (n = 30). Twenty-seven percent (20/74) of participants, however, had anti-PRP concentrations <1.0 µg/mL. Four weeks after the booster dose of HibCV, 98.5% of infants had anti-PRP concentrations above 1.0 µg/mL. CONCLUSION: Immunization with HibCV given as part of the Expanded Program on Immunization schedule in Nepal elicits robust antibody responses. Though the antibody wanes during the first year of life, most 1-year-old infants remain protected and respond robustly to a booster dose of the vaccine.

The kinetics and phenotype of the human B-cell response following immunization with a heptavalent pneumococcal-CRM conjugate vaccine.

Primary immunization of infants with protein-polysaccharide conjugate vaccines induces antipolysaccharide antibody and is highly effective in preventing invasive disease caused by encapsulated bacteria. However, recent experience from the UK indicates that this immunity is not sustained in the absence of booster doses of vaccine. This study aimed to establish the kinetics and phenotype of B-cell subpopulations responding to booster immunization with a heptavalent pneumococcal conjugate vaccine (Pnc7), which is to be introduced into the primary immunization schedule in the UK during 2006. Six adult volunteers received a booster dose of Pnc7 12-18 months after primary immunization. CD27hi CD38hi CD20(+/-) IgG antibody-forming cells were detected in peripheral blood with maximum frequency at days 6-7 after immunization. This was accompanied by a more prolonged rise in memory B cells that required in vitro stimulation with Staphylococcus aureus Cowan strain and interleukin-2 to induce antibody secretion. These data provide evidence for at least two subsets of antibody-forming cells involved in the secondary humoral response to a glycoconjugate vaccine in primed individuals. A briefly circulating subset of B cells that spontaneously secrete immunoglobulin G may be responsible for early defence against re-encountered encapsulated bacteria. However, the kinetics of the appearance of these cells may indicate that the humoral immune response is too slow in defence against an organism that invades within days of acquisition. The more sustained presence of a memory population may provide persistence of antipolysaccharide antibody after a booster dose of vaccine and may also include re-circulatory populations responsible for further anamnestic responses.