A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoprotein.

BACKGROUND: The development of a universal influenza virus vaccine, to protect against both seasonal and pandemic influenza A viruses, is a long-standing public health goal. The conserved stalk domain of haemagglutinin (HA) is a promising vaccine target. However, the stalk is immunosubdominant. As such, innovative approaches are required to elicit robust immunity against this domain. In a previously reported observer-blind, randomised placebo-controlled phase I trial (NCT03300050), immunisation regimens using chimeric HA (cHA)-based immunogens formulated as inactivated influenza vaccines (IIV) -/+ AS03 adjuvant, or live attenuated influenza vaccines (LAIV), elicited durable HA stalk-specific antibodies with broad reactivity. In this study, we sought to determine if these vaccines could also boost T cell responses against HA stalk, and nucleoprotein (NP). METHODS: We measured interferon-γ (IFN-γ) responses by Enzyme-Linked ImmunoSpot (ELISpot) assay at baseline, seven days post-prime, pre-boost and seven days post-boost following heterologous prime:boost regimens of LAIV and/or adjuvanted/unadjuvanted IIV-cHA vaccines. FINDINGS: Our findings demonstrate that immunisation with adjuvanted cHA-based IIVs boost HA stalk-specific and NP-specific T cell responses in humans. To date, it has been unclear if HA stalk-specific T cells can be boosted in humans by HA-stalk focused universal vaccines. Therefore, our study will provide valuable insights for the design of future studies to determine the precise role of HA stalk-specific T cells in broad protection. INTERPRETATION: Considering that cHA-based vaccines also elicit stalk-specific antibodies, these data support the further clinical advancement of cHA-based universal influenza vaccine candidates. FUNDING: This study was funded in part by the Bill and Melinda Gates Foundation (BMGF).

No immunological interference or concerns about safety when seasonal quadrivalent influenza vaccine is co-administered with a COVID-19 mRNA-1273 booster vaccine in adults: A randomized trial.

The objective of the study was to assess the safety and immunogenicity of mRNA-1273 COVID-19 booster vaccination when co-administered with an egg-based standard dose seasonal quadrivalent influenza vaccine (QIV). This was a phase 3, randomized, open-label study. Eligible adults aged ≥ 18 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and QIV 2 weeks apart (Seq group) or concomitantly (Coad group). Primary objectives were non-inferiority of haemagglutinin inhibition (HI) and anti-Spike protein antibody responses in the Coad compared to Seq group. 497/498 participants were randomized and vaccinated in the Seq/Coad groups, respectively. The adjusted geometric mean titer/concentration ratios (95% confidence intervals) (Seq/Coad) for HI antibodies were 1.02 (0.89-1.18) for A/H1N1, 0.93 (0.82-1.05) for A/H3N2, 1.00 (0.89-1.14] for B/Victoria, and 1.04 (0.93-1.17) for B/Yamagata; and 0.98 (0.84-1.13) for anti-Spike antibodies, thus meeting the protocol-specified non-inferiority criteria. The most frequently reported adverse events in both groups were pain at the injection site and myalgia. The 2 groups were similar in terms of the overall frequency, intensity, and duration of adverse events. In conclusion, co-administration of mRNA-1273 booster vaccine with QIV in adults was immunologically non-inferior to sequential administration. Safety and reactogenicity profiles were similar in both groups (clinicaltrials.gov NCT05047770).

What is the context? Updated booster shots against COVID-19 disease are likely to offer more protection as the virus is changing over time.It is important for doctors, other healthcare providers and patients to know whether COVID-19 booster vaccines can be given at the same time as other vaccines recommended for adults.What is new? The results of our study showed that an mRNA-based COVID-19 booster vaccine could be given at the same time as the seasonal influenza vaccine.When given together, both vaccines led to immune responses and had side effects that were similar to those observed when they were given at separate times.What is the impact? The potential benefits of administering more than 1 vaccine during a healthcare visit include improved coverage and a reduced number of doctor visits needed to receive all vaccines.Co-administration of COVID-19 booster vaccines and influenza vaccines could be an attractive option for patients and healthcare professionals.

Recombinant zoster vaccine in immunocompetent and immunocompromised adults: A review of clinical studies.

Herpes zoster (HZ) is a debilitating vaccine-preventable disease. Impairment of cell-mediated immunity, as observed with aging and immunosuppressive disorders and therapies, increases risk. Recombinant zoster vaccine (RZV) is efficacious against HZ in adults aged ≥50 years in different settings, and in immunocompromised adults aged ≥18 years who are at increased risk of developing HZ. RZV is the first and only HZ vaccine approved for use in immunocompromised adults globally, including in Europe and the US. RZV has a clinically acceptable safety profile and elicits robust immune responses in adults aged ≥50 years, and in immunocompromised adults aged ≥18 years who are at increased risk of HZ. Additionally, RZV is efficacious against HZ complications such as post-herpetic neuralgia and HZ-related pain. This review updates knowledge from a randomized controlled trial setting on the efficacy, safety, immunogenicity, and impact on quality of life of RZV.

What is the context?The varicella zoster virus, which causes chickenpox in childhood, can reactivate in adults and trigger a painful rash called herpes zoster (HZ) or shingles. Almost all adults are at risk of developing HZ as they age or develop risk factors for HZ. Two key studies published in 2015 and 2016 (ZOE-50 and ZOE-70) compared the recombinant zoster vaccine (RZV) with placebo and showed that RZV could effectively prevent HZ in adults aged ≥50 years and ≥70 years, respectively. Several clinical studies were carried out in subsequent years, assessing how effective and safe RZV is compared with a placebo/control in different populations. Based on these studies, RZV was approved for use in adults aged ≥50 years and those aged ≥18 years at increased risk of HZ (European Union) due to immunodeficiency or immunosuppression caused by known disease or therapy (United States).What is new?We reviewed clinical studies of RZV published between 1 January, 2015 and 31 October, 2022. The evidence shows that RZV is effective and does not cause safety concerns across the studied populations, including adults aged ≥50 years and immunocompromised adults aged ≥18 years who are at increased risk of HZ.What is the impact?The growing amount of knowledge on the efficacy, safety, immunogenicity, and impact on quality of life of RZV should assist in deciding to vaccinate and in ensuring that the individuals who could benefit the most from RZV have access to vaccination.

No Immunological Interference or Safety Concerns When Adjuvanted Recombinant Zoster Vaccine Is Coadministered With a Coronavirus Disease 2019 mRNA-1273 Booster Vaccine in Adults Aged 50 Years and Older: A Randomized Trial.

BACKGROUND: There is growing consensus that coronavirus disease 2019 booster vaccines may be coadministered with other age-appropriate vaccines. Adding to the limited available data supporting coadministration, especially with adjuvanted vaccines, could enhance vaccine coverage in adults. METHODS: In this phase 3, randomized, open-label study, eligible adults aged ≥50 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and a first dose of recombinant zoster vaccine (RZV1) 2 weeks apart (Seq group) or concomitantly (Coad group). The second RZV dose (RZV2) was administered 2 months post-RZV1 in both groups. Primary objectives were noninferiority of anti-glycoprotein E (gE) and anti-spike protein antibody responses in the Coad group compared to the Seq group. Safety and further immunogenicity assessments were secondary objectives. RESULTS: In total, 273 participants were randomized to the Seq group and 272 to the Coad group. Protocol-specified noninferiority criteria were met. The adjusted geometric mean concentration ratio (Seq/Coad) was 1.01 (95% confidence interval [CI], .89-1.13) for anti-gE antibodies 1 month post-RZV2, and 1.09 (95% CI, .90-1.32) for anti-spike antibodies 1 month post-mRNA-1273 booster. No clinically relevant differences were observed in overall frequency, intensity, or duration of adverse events between the 2 study groups. Most solicited adverse events were mild/moderate in intensity, each with median duration ≤2.5 days. Administration site pain and myalgia were the most frequently reported in both groups. CONCLUSIONS: Coadministration of mRNA-1273 booster vaccine with RZV in adults aged ≥50 years was immunologically noninferior to sequential administration and had a safety and reactogenicity profile consistent with both vaccines administered sequentially. Clinical Trials Registration. NCT05047770.

Meningococcal ACWYX Conjugate Vaccine in 2-to-29-Year-Olds in Mali and Gambia.

BACKGROUND: An effective, affordable, multivalent meningococcal conjugate vaccine is needed to prevent epidemic meningitis in the African meningitis belt. Data on the safety and immunogenicity of NmCV-5, a pentavalent vaccine targeting the A, C, W, Y, and X serogroups, have been limited. METHODS: We conducted a phase 3, noninferiority trial involving healthy 2-to-29-year-olds in Mali and Gambia. Participants were randomly assigned in a 2:1 ratio to receive a single intramuscular dose of NmCV-5 or the quadrivalent vaccine MenACWY-D. Immunogenicity was assessed at day 28. The noninferiority of NmCV-5 to MenACWY-D was assessed on the basis of the difference in the percentage of participants with a seroresponse (defined as prespecified changes in titer; margin, lower limit of the 96% confidence interval [CI] above -10 percentage points) or geometric mean titer (GMT) ratios (margin, lower limit of the 98.98% CI >0.5). Serogroup X responses in the NmCV-5 group were compared with the lowest response among the MenACWY-D serogroups. Safety was also assessed. RESULTS: A total of 1800 participants received NmCV-5 or MenACWY-D. In the NmCV-5 group, the percentage of participants with a seroresponse ranged from 70.5% (95% CI, 67.8 to 73.2) for serogroup A to 98.5% (95% CI, 97.6 to 99.2) for serogroup W; the percentage with a serogroup X response was 97.2% (95% CI, 96.0 to 98.1). The overall difference between the two vaccines in seroresponse for the four shared serogroups ranged from 1.2 percentage points (96% CI, -0.3 to 3.1) for serogroup W to 20.5 percentage points (96% CI, 15.4 to 25.6) for serogroup A. The overall GMT ratios for the four shared serogroups ranged from 1.7 (98.98% CI, 1.5 to 1.9) for serogroup A to 2.8 (98.98% CI, 2.3 to 3.5) for serogroup C. The serogroup X component of the NmCV-5 vaccine generated seroresponses and GMTs that met the prespecified noninferiority criteria. The incidence of systemic adverse events was similar in the two groups (11.1% in the NmCV-5 group and 9.2% in the MenACWY-D group). CONCLUSIONS: For all four serotypes in common with the MenACWY-D vaccine, the NmCV-5 vaccine elicited immune responses that were noninferior to those elicited by the MenACWY-D vaccine. NmCV-5 also elicited immune responses to serogroup X. No safety concerns were evident. (Funded by the U.K. Foreign, Commonwealth, and Development Office and others; ClinicalTrials.gov number, NCT03964012.).

Meningococcal Serogroup ACWYX Conjugate Vaccine in Malian Toddlers.

BACKGROUND: Neisseria meningitidis serogroups A, B, C, W, X, and Y cause outbreaks of meningococcal disease. Quadrivalent conjugate vaccines targeting the A, C, W, and Y serogroups are available. A pentavalent vaccine that also includes serogroup X (NmCV-5) is under development. METHODS: We conducted a phase 2, observer-blinded, randomized, controlled trial involving Malian children 12 to 16 months of age. Participants were assigned in a 2:2:1 ratio to receive nonadjuvanted NmCV-5, alum-adjuvanted NmCV-5, or the quadrivalent vaccine MenACWY-D, administered intramuscularly in two doses 12 weeks apart. Participants were followed for safety for 169 days. Immunogenicity was assessed with an assay for serum bactericidal antibody (SBA) with rabbit complement on days 0, 28, 84, and 112. RESULTS: A total of 376 participants underwent randomization, with 150 assigned to each NmCV-5 group and 76 to the MenACWY-D group; 362 participants received both doses of vaccine. A total of 1% of the participants in the nonadjuvanted NmCV-5 group, 1% of those in the adjuvanted NmCV-5 group, and 4% of those in the MenACWY-D group reported local solicited adverse events; 6%, 5%, and 7% of the participants, respectively, reported systemic solicited adverse events. An SBA titer of at least 128 was seen in 91 to 100% (for all five serotypes) of the participants in the NmCV-5 groups and in 36 to 99% (excluding serogroup X) of those in the MenACWY-D group at day 84 (before the second dose); the same threshold was met in 99 to 100% (for all five serotypes) of the participants in the NmCV-5 groups and in 92 to 100% (excluding serogroup X) of those in the MenACWY-D group at day 112. Immune responses to the nonadjuvanted and adjuvanted NmCV-5 formulations were similar. CONCLUSIONS: No safety concerns were identified with two doses of NmCV-5. A single dose of NmCV-5 elicited immune responses that were similar to those observed with two doses of MenACWY-D. Adjuvanted NmCV-5 provided no discernible benefit over nonadjuvanted NmCV-5. (Funded by the U.K. Foreign, Commonwealth, and Development Office; ClinicalTrials.gov number, NCT03295318.).

Safety, reactogenicity, and immunogenicity of a chimpanzee adenovirus vectored Ebola vaccine in adults in Africa: a randomised, observer-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The 2014 Zaire Ebola virus disease epidemic accelerated vaccine development for the virus. We aimed to assess the safety, reactogenicity, and immunogenicity of one dose of monovalent, recombinant, chimpanzee adenovirus type-3 vectored Zaire Ebola glycoprotein vaccine (ChAd3-EBO-Z) in adults. METHODS: This phase 2, randomised, observer-blind, controlled trial was done in study centres in Cameroon, Mali, Nigeria, and Senegal. Healthy adults (≥18 years) were randomly assigned with a web-based system (1:1; minimisation procedure accounting for age, gender, centre) to receive ChAd3-EBO-Z (day 0), or saline placebo (day 0) and ChAd3-EBO-Z (month 6). The study was observer-blind until planned interim day 30 analysis, single-blind until month 6, and open-label after month 6 vaccination. Primary outcomes assessed in the total vaccinated cohort, which comprised all participants with at least one study dose administration documented, were serious adverse events (up to study end, month 12); and for a subcohort were solicited local or general adverse events (7 days post-vaccination), unsolicited adverse events (30 days post-vaccination), haematological or biochemical abnormalities, and clinical symptoms of thrombocytopenia (day 0-6). Secondary endpoints (subcohort; per-protocol cohort) evaluated anti-glycoprotein Ebola virus antibody titres (ELISA) pre-vaccination and 30 days post-vaccination. This study is registered with ClinicalTrials.gov, NCT02485301. FINDINGS: Between July 22, 2015, and Dec 10, 2015, 3030 adults were randomly assigned; 3013 were included in the total vaccinated cohort (1509 [50·1%] in the ChAd3-EBO-Z group and 1504 [49·9%] in the placebo/ChAd3-EBO-Z group), 17 were excluded because no vaccine was administered. The most common solicited injection site symptom was pain (356 [48%] of 748 in the ChAd3-EBO-Z group vs 57 [8%] of 751 in the placebo/ChAd3-EBO-Z group); the most common solicited general adverse event was headache (345 [46%] in the ChAd3-EBO-Z group vs 136 [18%] in the placebo/ChAd3-EBO-Z group). Unsolicited adverse events were reported by 123 (16%) of 749 in the ChAd3-EBO-Z group and 119 (16%) of 751 in the placebo/ChAd3-EBO-Z group. Serious adverse events were reported for 11 (1%) of 1509 adults in the ChAd3-EBO-Z group, and 18 (1%) of 1504 in the placebo/ChAd3-EBO-Z group; none were considered vaccination-related. No clinically meaningful thrombocytopenia was reported. At day 30, anti-glycoprotein Ebola virus antibody geometric mean concentration was 900 (95% CI 824-983) in the ChAd3-EBO-Z group. There were no treatment-related deaths. INTERPRETATION: ChAd3-EBO-Z was immunogenic and well tolerated in adults. Our findings provide a strong basis for future development steps, which should concentrate on multivalent approaches (including Sudan and Marburg strains). Additionally, prime-boost approaches should be a focus with a ChAd3-based vaccine for priming and boosted by a modified vaccinia Ankara-based vaccine. FUNDING: EU's Horizon 2020 research and innovation programme and GlaxoSmithKline Biologicals SA.