Safety and effectiveness of a recombinant hepatitis E vaccine in women of childbearing age in rural Bangladesh: a phase 4, double-blind, cluster-randomised, controlled trial.

BACKGROUND: Hepatitis E virus (HEV) leads to high mortality in pregnant women in low-income countries. We aimed to evaluate the safety of a HEV vaccine and its effectiveness in preventing hepatitis E during pregnancy. METHODS: In this phase 4, double-blind, cluster-randomised trial, 67 villages in Matlab, Bangladesh, were randomised 1:1 to receive HEV239 (a recombinant HEV vaccine) or a control vaccine (Hepa-B, a hepatitis B vaccine), using block randomisation with random number tables and blocks of size eight, stratified by cluster population size. Eligible non-pregnant women (aged 16-39 years) were vaccinated intramuscularly on day 0, at 1 month, and at 6 months, and followed up for 2 years after the last immunisation. The primary endpoint was hepatitis E in the pregnant, per-protocol population (those who received all three doses within 2 days of the scheduled dates), while safety was a secondary endpoint, assessed in the intention-to-treat (ITT) population (participants who received at least one dose). Solicited adverse events were recorded for the first 7 days after each dose, and unsolicited events until 2 years after a participant's final dose. Pregnancy-related safety outcomes were assessed in the pregnant ITT population. This study is registered with ClinicalTrials.gov (NCT02759991). FINDINGS: Between Oct 2, 2017, and Feb 28, 2019, 19 460 participants were enrolled and received either HEV239 (9478 [48·7%] participants, 33 clusters) or Hepa-B (9982 [51·3%] participants, 34 clusters), of whom 17 937 (92·2%) participants received three doses and 17 613 (90·5%) were vaccinated according to protocol (8524 [48·4%] in the HEV239 group and 9089 [51·6%] in the control group). No pregnant participants were confirmed to have hepatitis E in either treatment group. HEV239 showed a mild safety profile, similar to Hepa-B, with no difference in the proportion of solicited adverse events between groups and no severe solicited events. Pain was the most common local symptom (1215 [12·8%] HEV239 recipients and 1218 [12·2%] Hepa-B recipients) and fever the most common systemic symptom (141 [1·5%] HEV239 recipients and 145 [1·5%] Hepa-B recipients). None of the serious adverse events or deaths were vaccine related. Among pregnant participants, the HEV239 group had a higher risk of miscarriage (136 [5·7%] of 2407 pregnant participants) compared with the control group (102 [3·9%] of 2604; adjusted odds ratio 1·54 [95% CI 1·15-2·08]). INTERPRETATION: The effectiveness of HEV239 in pregnant women remains uncertain. HEV239 was safe and well tolerated in non-pregnant women, but findings regarding miscarriage warrant further investigation. FUNDING: Research Council of Norway; Innovax.

Immunogenicity and Safety of Heterologous Omicron BA.1 and Bivalent SARS-CoV-2 Recombinant Spike Protein Booster Vaccines: A Phase 3 Randomized Clinical Trial.

BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or the bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 41.4-60.3) for NVX-CoV2373. All formulations were similarly well tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT05372588).

Safety concern of recombination between self-amplifying mRNA vaccines and viruses is mitigated in vivo.

Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is the potential for recombination between alphavirus-based SAM vaccines and circulating viruses. This theoretical risk needs to be assessed in the regulatory process for SAM vaccine approval. Herein, we undertake extensive in vitro and in vivo assessments to explore recombination between SAM vaccine and a wide selection of alphaviruses and a coronavirus. SAM vaccines were found to effectively limit alphavirus co-infection through superinfection exclusion, although some co-replication was still possible. Using sensitive cell-based assays, replication-competent alphavirus chimeras were generated in vitro as a result of rare, but reproducible, RNA recombination events. The chimeras displayed no increased fitness in cell culture. Viable alphavirus chimeras were not detected in vivo in C57BL/6J, Rag1-/- and Ifnar-/- mice, in which high levels of SAM vaccine and alphavirus co-replicated in the same tissue. Furthermore, recombination between a SAM-spike vaccine and a swine coronavirus was not observed. In conclusion we state that although the ability of SAM vaccines to recombine with alphaviruses might be viewed as an environmental safety concern, several key factors substantially mitigate against in vivo emergence of chimeric viruses from SAM vaccine recipients.

Immunogenicity and safety evaluation of a newly manufactured recombinant Baculovirus-Expressed quadrivalent influenza vaccine in adults 18 years old and Above: An Open-Label, phase III extension study.

In the face of global health threats, there is a growing demand for vaccines that can be manufactured on a large scale within compressed timeline. This study responds to this imperative by delving into the evaluation of FluGuard, a novel recombinant influenza vaccine developed by Nivad Pharmed Salamat Company in Iran. Positioned as a phase 3 extension, the research aimed to evaluate the safety and immunogenicity of FluGuard in volunteers aged 18 and above. The study was conducted as a single-center, open-label clinical trial. All eligible volunteers received FluGuard (2021-2022 Formula) on day 0. Safety assessments occurred at days 1, 4, 7, 14, 28 and 42 post-vaccination. Immunogenicity was measured through seroconversion, seroprotection, and geometric mean titer fold increase in subgroups of 250 volunteers. Among the 4,260 volunteers were screened and assessed for eligibility, 1000 were enrolled. At day 28 post-vaccination, seroconversion rates for A/H1N1, A/H3N2, B/Yamagata, B/Victoria were 53.4 % [95 %CI: 46.7-60], 57.7 % [95 %CI: 51.1-64.3], 54.3 % [95 %CI: 47.7-60.9], and 36.2 % [95 %CI: 29.8-42.6], respectively in volunteers 18 years and above. The most common solicited adverse events were pain at the injection site, malaise, and headache. No suspected unexpected adverse events and adverse events of special interest occurred during the study period. Our findings suggested that FluGuard® exhibits a desirable safety profile and provides sufficient immunogenicity against influenza virus types A and B. However, extended studies are warranted to assess the long-term protective efficacy. Trial Registration: The study protocol was accepted by Iranian registry of clinical trial; https://www.irct.ir; IRCT20201104049265N2.

Efficacy, safety, and immunogenicity of SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012: a randomized, double-blind, placebo-controlled phase 3 trial.

Background: We aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in China. Methods: This is a single-center, randomized, double-blind, placebo-controlled phase 3 clinical trial enrolling healthy adult participants (≥18 years) who had completed two or three doses of inactivated COVID-19 vaccines at least 6 months before, in Bengbu, Anhui province, China. Eligible participants were randomly assigned (1:1) to receive a booster intramuscular vaccination with an LVRNA012 vaccine (100ug) or placebo. The primary endpoint was the protective efficacy of a booster dose of the LVRNA012 vaccine or placebo against symptomatic COVID-19 of any severity 14 days after vaccination. Laboratory-confirmed COVID-19 infections were identified from 14 days to 180 days after intervention, with active surveillance for symptomatic illness 8 times per month between 7 to 90 days and at least once per month between 90 to 180 days after intervention. Results: 2615 participants were recruited and randomly assigned in a 1:1 ratio to either the vaccine group (1308) or the placebo group (1307). A total of 141 individuals (46 in the LVRNA012 group and 95 in the placebo group) developed symptomatic COVID-19 infection 14 days after the booster immunization, showing a vaccine efficacy of 51.9% (95% CI, 31.3% to 66.4%). Most infections were detected 90 days after intervention during a period when XBB was prevalent in the community. Adverse reactions were reported by 64% of participants after the LVRNA012 vaccination, but most of them were mild or moderate. The booster vaccination with the LVRNA012 mRNA vaccine could significantly enhance neutralizing antibody titers against the Omicron variant XBB.1.5 (GMT 132.3 [99.8, 175.4]) than did those in the placebo group (GMT 12.5 [8.4, 18.7]) at day 14 for the previously immunized individuals. Conclusion: The LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period. Clinical trial registration: ClinicalTrials.gov, identifier NCT05745545.

The safety, immunogenicity, and efficacy of heterologous boosting with a SARS-CoV-2 mRNA vaccine (SYS6006) in Chinese participants aged 18 years or more: a randomized, open-label, active-controlled phase 3 trial.

Continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enhanced transmissibility, significant immune escape, and waning immunity call for booster vaccination. We evaluated the safety, immunogenicity, and efficacy of heterologous booster with a SARS-CoV-2 mRNA vaccine SYS6006 versus an active control vaccine in a randomized, open-label, active-controlled phase 3 trial in healthy adults aged 18 years or more who had received two or three doses of SARS-CoV-2 inactivated vaccine in China. The trial started in December 2022 and lasted for 6 months. The participants were randomized (overall ratio: 3:1) to receive one dose of SYS6006 (N = 2999) or an ancestral receptor binding region-based, alum-adjuvanted recombinant protein SARS-CoV-2 vaccine (N = 1000), including 520 participants in an immunogenicity subgroup. SYS6006 boosting showed good safety profiles with most AEs being grade 1 or 2, and induced robust wild-type and Omicron BA.5 neutralizing antibody response on Days 14 and 28, demonstrating immunogenicity superiority versus the control vaccine and meeting the primary objective. The relative vaccine efficacy against COVID-19 of any severity was 51.6% (95% CI, 35.5-63.7) for any variant, 66.8% (48.6-78.5) for BA.5, and 37.7% (2.4-60.3) for XBB, from Day 7 through Month 6. In the vaccinated and infected hybrid immune participants, the relative vaccine efficacy was 68.4% (31.1-85.5) against COVID-19 of any severity caused by a second infection. All COVID-19 cases were mild. SYS6006 heterologous boosting demonstrated good safety, superior immunogenicity and high efficacy against BA.5-associated COVID-19, and protected against XBB-associated COVID-19, particularly in the hybrid immune population.Trial registration: Chinese Clinical Trial Registry: ChiCTR2200066941.

Efficacy, reactogenicity, and safety of the adjuvanted recombinant zoster vaccine for the prevention of herpes zoster in Chinese adults ≥ 50 years: A randomized, placebo-controlled trial.

Phase III multi-country studies (ZOE-50/70) demonstrated that the adjuvanted recombinant zoster vaccine (RZV) was well tolerated and prevented herpes zoster (HZ) in healthy ≥ 50-year-olds, with a vaccine efficacy (VE) > 90% across age groups. These pivotal trials did not enroll participants from mainland China where RZV is licensed, therefore similar clinical data are missing for this population. In this phase IV observer-blind study (NCT04869982) conducted between 2021 and 2023 in China, immunocompetent and medically stable ≥ 50-year-olds were randomized 1:1 to receive two RZV or placebo doses, 2 months apart. This study assessed the VE (overall, as confirmatory objective, and descriptively by age category [50-69-year-olds/≥ 70-year-olds]), reactogenicity, and safety of RZV in this Chinese population. Of the 6138 enrolled participants, 99.2% completed the study. During a mean follow-up period of 15.2 (±1.1) months, 31 HZ episodes were confirmed (RZV = 0; placebo = 31) for an incidence rate of 0.0 vs 8.2 per 1000 person-years and an overall VE of 100% (89.82-100). The descriptive VE was 100% (85.29-100) for 50-69-year-olds and 100% (60.90-100) for ≥ 70-year-olds. Solicited adverse events (AEs) were more frequent in the RZV vs the placebo group (median duration: 1-3 days for both groups). Pain and fatigue were the most frequent local and general AEs (RZV: 72.1% and 43.4%; placebo: 9.2% and 5.3%). The frequencies of unsolicited AEs, serious AEs, potential immune-mediated diseases, and deaths were similar between both groups. RZV is well tolerated and efficacious in preventing HZ in Chinese ≥ 50-year-olds, consistent with efficacy studies including worldwide populations with similar age and medical characteristics.

What is the context? Herpes zoster, commonly known as shingles, is a painful rash resulting from the reactivation of the dormant virus causing chickenpox.Vaccines preventing shingles, such as Shingrix, were shown to be well tolerated and efficacious in healthy adults over 50 years of age from Europe, North and Latin America, Australia, and Asia (Taiwan, Hong Kong, Korea, Japan).However, data on real-world protective effect of Shingrix are limited in some regions where the vaccine is licensed for use, such as mainland China.What is new? We analyzed data from Chinese adults aged 50 years or older to determine the efficacy and safety of Shingrix.Around 6000 participants were divided in two equal groups to receive two doses of Shingrix or two doses of a placebo, given 2 months apart.We found that, during the study period, the vaccine was 100% efficacious in preventing shingles.We showed that the vaccine had an acceptable safety profile in this Chinese population.What is the impact? Shingrix is efficacious and well tolerated in Chinese adults over 50 years of age, as it is in similarly aged populations from other evaluated regions.

A SARS-CoV-2 recombinant spike protein vaccine (S-268019-b) for COVID-19 prevention during the Omicron-dominant period: A phase 3, randomised, placebo-controlled clinical trial.

Clinical trials of new vaccines based on existing variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are often impacted by the emergence of new virus variants. We evaluated the efficacy, immunogenicity, and safety of S-268019-b, a recombinant spike protein subunit vaccine based on the ancestral strain, for preventing symptomatic coronavirus disease 2019 (COVID-19) during the Omicron (BA.2)-dominant period in Vietnam. In this multicentre, phase 3, randomised (2:1), observer-blind, placebo-controlled crossover study, participants received 2 intramuscular doses (28 days apart) of either 10 µg of S-268019-b (Recombinant S-protein vaccine) or placebo. The primary endpoint was incidence of laboratory-confirmed symptomatic COVID-19 before crossover, with onset within 14 days following the second dose, in participants who were seronegative and reverse transcription polymerase chain reaction (RT-PCR)-negative at baseline. The secondary endpoints included immunogenicity and safety. In total, 8,594 participants were randomised (S-268019-b [n = 5,727]; placebo [n = 2,867]). Vaccine efficacy versus placebo was 39·1 % (95 % confidence interval [CI]:26·6-49·5; one-sided P = 0·0723). The incidence rate (95 % CI) of symptomatic COVID-19 was 776·41/1,000 person-years (682·04-880·19) in the S-268019-b group and 1272·87/1,000 person-years (1101·32-1463·57) in the placebo group. The geometric mean titres (95 % CI) of the SARS-CoV-2 neutralising antibody increased on Day 57 versus baseline with S-268019-b (34·66 [27·04-44·41] versus 2·50 (non-estimable) but not with placebo. There were no safety concerns regarding S-268019-b. S-268019-b did not demonstrate the targeted efficacy threshold against symptomatic COVID-19; however, findings were comparable with other prophylactic vaccines based on ancestor strain during the Omicron-dominant period. S-268019-b demonstrated immunogenicity and was well-tolerated. ClinicalTrials.gov identifier: NCT05212948.

Safety, immunogenicity and protective effect of sequential vaccination with inactivated and recombinant protein COVID-19 vaccine in the elderly: a prospective longitudinal study.

The safety and efficacy of COVID-19 vaccines in the elderly, a high-risk group for severe COVID-19 infection, have not been fully understood. To clarify these issues, this prospective study followed up 157 elderly and 73 young participants for 16 months and compared the safety, immunogenicity, and efficacy of two doses of the inactivated vaccine BBIBP-CorV followed by a booster dose of the recombinant protein vaccine ZF2001. The results showed that this vaccination protocol was safe and tolerable in the elderly. After administering two doses of the BBIBP-CorV, the positivity rates and titers of neutralizing and anti-RBD antibodies in the elderly were significantly lower than those in the young individuals. After the ZF2001 booster dose, the antibody-positive rates in the elderly were comparable to those in the young; however, the antibody titers remained lower. Gender, age, and underlying diseases were independently associated with vaccine immunogenicity in elderly individuals. The pseudovirus neutralization assay showed that, compared with those after receiving two doses of BBIBP-CorV priming, some participants obtained immunological protection against BA.5 and BF.7 after receiving the ZF2001 booster. Breakthrough infection symptoms last longer in the infected elderly and pre-infection antibody titers were negatively associated with the severity of post-infection symptoms. The antibody levels in the elderly increased significantly after breakthrough infection but were still lower than those in the young. Our data suggest that multiple booster vaccinations at short intervals to maintain high antibody levels may be an effective strategy for protecting the elderly against COVID-19.

Immunogenicity and safety of a recombinant Omicron BA.4/5-Delta COVID-19 vaccine ZF2202-A in Chinese adults.

BACKGROUND: The Recombinant Omicron BA.4/5-Delta COVID-19 Vaccine (ZF2202-A) is primarily designed for the Delta and Omicron BA.4/5 variants. Our objective was to assess the safety and immunogenicity of ZF2202-A in Chinese adults. METHODS: A total of 450 participants aged ≥ 18 years, who had completed primary or booster vaccination with a COVID-19 vaccine more than 6 months prior, were enrolled in this randomized, double-blind, active-controlled trial. Participants in the study and control groups were administered one dose of ZF2202-A and ZF2001, respectively. Immunogenicity subgroups were established in each group. RESULTS: At 14 days after vaccination, the seroconversion rates of Omicron BA.4/5, BF.7, and XBB.1 in the ZF2022-A group were 67.7 %, 58.6 %, and 62.6 %, with geometric mean titers (GMTs) of neutralizing antibodies at 350.2, 491.8, and 49.5, respectively. The main adverse reactions (ARs) were vaccination site pain, pruritus, fatigue, and asthenia in both the ZF2022-A group and ZF2001 group. CONCLUSIONS: The novel bivalent vaccine ZF2202-A demonstrated satisfactory immunogenicity and safety against Omicron variants as booster dose in adults with prior vaccination of COVID-19 vaccines.

Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a and 3b randomized, controlled trials.

Combination of waning immunity and lower effectiveness against new SARS-CoV-2 variants of approved COVID-19 vaccines necessitates new vaccines. We evaluated two doses, 28 days apart, of ARCT-154, a self-amplifying mRNA COVID-19 vaccine, compared with saline placebo in an integrated phase 1/2/3a/3b controlled, observer-blind trial in Vietnamese adults (ClinicalTrial.gov identifier: NCT05012943). Primary safety and reactogenicity outcomes were unsolicited adverse events (AE) 28 days after each dose, solicited local and systemic AE 7 days after each dose, and serious AEs throughout the study. Primary immunogenicity outcome was the immune response as neutralizing antibodies 28 days after the second dose. Efficacy against COVID-19 was assessed as primary and secondary outcomes in phase 3b. ARCT-154 was well tolerated with generally mild-moderate transient AEs. Four weeks after the second dose 94.1% (95% CI: 92.1-95.8) of vaccinees seroconverted for neutralizing antibodies, with a geometric mean-fold rise from baseline of 14.5 (95% CI: 13.6-15.5). Of 640 cases of confirmed COVID-19 eligible for efficacy analysis most were due to the Delta (B.1.617.2) variant. Efficacy of ARCT-154 was 56.6% (95% CI: 48.7- 63.3) against any COVID-19, and 95.3% (80.5-98.9) against severe COVID-19. ARCT-154 vaccination is well tolerated, immunogenic and efficacious, particularly against severe COVID-19 disease.

Safety profile of recombinant adjuvanted anti-herpes zoster vaccine (RZV) in high-risk groups: Data from active surveillance program. Puglia (Italy), 2021-23.

BACKGROUND: Since 2021 a recombinant adjuvanted anti-Herpes Zoster vaccine(Recombinant Zoster Vaccine, RZV) is offered in Italy to high-risk patients. Few real-life data about RZV safety are available in target populations. OBJECTIVES: This study investigates Adverse Events Following Immunization(AEFIs), baseline disease flare-ups, and Herpes Zoster (HZ) episodes occurring after RZV administration in a heterogeneous population of fragile patients to design its safety profile. METHODS: This is a retrospective population-based study. RZV-vaccinated patients at Bari Policlinico General Hospital vaccination clinic from October 1st, 2021, to March 31st, 2023, were enrolled. Subjects were screened for reason of RZV eligibility and baseline chronic pathologies. AEFIs occurred in the first 7-days post-vaccination period were collected, and baseline disease flare-ups and post-vaccination HZ episodes were assessed via a 3-month follow-up. RESULTS: Five-hundred-thirty-eight patients were included and total of 1,031 doses were administered. Most patients were vaccinated due to ongoing immunosuppressive therapy(54.65 %); onco-hematological and cardiovascular conditions were the most common chronic baseline pathologies. Out of 1,031 follow-ups, 441 AEFI cases were reported(42.7/100). The most common symptoms were injection site pain/itching(35.60/100), asthenia/malaise(11.44/100), and fever (10.09/100). Four serious AEFIs occurred(0.38/100). Older age, male sex, and history of cardiovascular diseases(OR:0.71; 95CI:0.52-0.98; p-value <0.05) were found to decrease AEFIs risk, while endocrine-metabolic illnesses(OR:1.61; 95CI:1.15-2.26; p-value <0.05) increased it. Twelve patients(2.23 %) reported a flare-up/worsening of their baseline chronic condition within the first three months after vaccination(mean interval 31.75 days, range 0-68 days). Patients with rheumatological illnesses had a higher risk of relapse(OR:16.56; 95CI:3.58-76.56; p-value <0.001), while male sex behaved as a protective factor. Twelve patients who completed the vaccination cycle(2.43%) had at least one HZ episode by the long-term follow-up. CONCLUSIONS: The study demonstrates RZV safety in a significant number of high-risk patients. Hence, RZV should be actively offered as part of tailored vaccination programs to decrease the burden of HZ in fragile populations.

Immunogenicity and safety of live attenuated and recombinant/inactivated varicella zoster vaccines in people living with HIV: A systematic review.

Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.

Immunogenicity and influence on disease activity of recombinant zoster vaccine in patients with rheumatoid arthritis treated with DMARDs.

OBJECTIVES: This study aimed to determine the immunogenicity and the influence on disease activity of an adjuvanted recombinant varicella-zoster virus (VZV) subunit vaccine (RZV) in patients with rheumatoid arthritis (RA) treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: This prospective longitudinal study enrolled 53 patients with RA (aged ≥50 years) treated with DMARDs (conventional synthetic (cs)DMARDs 20, biological (b)DMARDs 23 and targeted synthetic (ts)DMARDs 10) and 10 control individuals. The participants received two intramuscular RZV 2 months apart. VZV-specific CD4+ T cell responses (cell-mediated immunity; CMI) and IgG antibody responses (humoral immunity; HI) were assessed at 0 and 3 months after the first RZV administration using flow cytometry and enzyme immunoassay, respectively. Disease activity (Disease Activity Score 28-C reactive protein and Clinical Disease Activity Index), flares and adverse events were monitored for 6 months after the first vaccination. RESULTS: VZV-specific CMI and HI significantly increased in the three DMARDs-treated patients with RA after RZV administration compared with the corresponding prevaccination values (p<0.001-0.014), and the magnitudes and fold-increases of those responses were not significantly different among the three DMARDs-treated patients with RA. Furthermore, the vaccine response rates of CMI and HI were not significantly different between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients. Meanwhile, no significant increases in disease activity indices or adverse events were observed in these patients during the 6-month follow-up period after the first vaccination. RZV-induced RA flares occurred in two patients (3.8%) but were mild and controllable. CONCLUSION: RZV is robustly immunogenic and has a clinically acceptable safety profile in elderly patients with RA receiving DMARDs.

Co-administration of the adjuvanted recombinant zoster vaccine with other adult vaccines: An overview.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV; Shingrix®, GSK) is a subunit vaccine that has been approved for the prevention of herpes zoster in adults. Co-administration of two vaccines in a single visit is a strategy to improve overall vaccine coverage. OBJECTIVES: This review aims to consolidate available clinical data on RZV co-administration, providing an overview of safety, reactogenicity and immunogenicity. METHODS: RZV co-administration data were obtained from five randomised, open-label, phase III clinical trials with similar study designs. The co-administered vaccines included: quadrivalent seasonal inactivated influenza vaccine (IIV4; NCT01954251), 23-valent pneumococcal polysaccharide vaccine (PPSV23; NCT02045836), reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine (Tdap; NCT02052596), 13-valent pneumococcal conjugate vaccine (PCV13; NCT03439657) and COVID-19 mRNA-1273 booster (NCT05047770). Eligible participants were healthy adults aged ≥50 years. RESULTS: A total of 3,974 participants were vaccinated (co-administration: 1,973; sequential: 2,001) across the five trials. Vaccine response rates to RZV were similar for co-administration (range: 95.8-99.1 %) and sequential groups (range: 95.1-99.1 %). Immune responses to RZV and the other vaccines (with the exception of pertactin) were non-inferior when the vaccines were co-administered compared with sequentially administered. Overall incidences of solicited local and general adverse events (AEs), unsolicited AEs, serious AEs or potential immune-mediated diseases were similar after co-administration or sequential administration. Myalgia was the most common solicited systemic AE (co-administration: 38-64 %; sequential: 30-59 %). Shivering and fever were more common after co-administration (16 % and 21 %, respectively) than after sequential administration (both 7 %) of RZV and PPSV23. CONCLUSIONS: Co-administration of RZV with routine vaccines does not significantly alter the reactogenicity, immunogenicity or safety of RZV or the co-administered vaccine. Healthcare practitioners should consider routine co-administration of RZV with other adult vaccines to improve vaccination coverage.

ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

INTRODUCTION: The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. METHODS: Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. RESULTS: Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). DISCUSSION: Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

Recombinant parainfluenza virus 5 expressing clade 2.3.4.4b H5 hemagglutinin protein confers broad protection against H5Ny influenza viruses.

The global circulation of clade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses (HPAIVs) in poultry and wild birds, increasing mammal infections, continues to pose a public health threat and may even form a pandemic. An efficacious vaccine against H5Ny HPAIVs is crucial for emergency use and pandemic preparedness. In this study, we developed a parainfluenza virus 5 (PIV5)-based vaccine candidate expressing hemagglutinin (HA) protein of clade 2.3.4.4b H5 HPAIV, termed rPIV5-H5, and evaluated its safety and efficacy in mice and ferrets. Our results demonstrated that intranasal immunization with a single dose of rPIV5-H5 could stimulate H5-specific antibody responses, moreover, a prime-boost regimen using rPIV5-H5 stimulated robust humoral, cellular, and mucosal immune responses in mice. Challenge study showed that rPIV5-H5 prime-boost regimen provided sterile immunity against lethal clade 2.3.4.4b H5N1 virus infection in mice and ferrets. Notably, rPIV5-H5 prime-boost regimen provided protection in mice against challenge with lethal doses of heterologous clades 2.2, 2.3.2, and 2.3.4 H5N1, and clade 2.3.4.4h H5N6 viruses. These results revealed that rPIV5-H5 can elicit protective immunity against a diverse clade of highly pathogenic H5Ny virus infection in mammals, highlighting the potential of rPIV5-H5 as a pan-H5 influenza vaccine candidate for emergency use.IMPORTANCEClade 2.3.4.4b H5Ny highly pathogenic avian influenza viruses (HPAIVs) have been widely circulating in wild birds and domestic poultry all over the world, leading to infections in mammals, including humans. Here, we developed a recombinant PIV5-vectored vaccine candidate expressing the HA protein of clade 2.3.4.4b H5 virus. Intranasal immunization with rPIV5-H5 in mice induced airway mucosal IgA responses, high levels of antibodies, and robust T-cell responses. Importantly, rPIV5-H5 conferred complete protection in mice and ferrets against clade 2.3.4.4b H5N1 virus challenge, the protective immunity was extended against heterologous H5Ny viruses. Taken together, our data demonstrate that rPIV5-H5 is a promising vaccine candidate against diverse H5Ny influenza viruses in mammals.

Recombinant Full-length Plasmodium falciparum Circumsporozoite Protein-Based Vaccine Adjuvanted With Glucopyranosyl Lipid A-Liposome Quillaja saponaria 21: Results of Phase 1 Testing With Malaria Challenge.

BACKGROUND: Malaria is preventable yet causes >600 000 deaths annually. RTS,S, the first marketed malaria vaccine, has modest efficacy, but improvements are needed for eradication. METHODS: We conducted an open-label, dose escalation phase 1 study of a full-length recombinant circumsporozoite protein vaccine (rCSP) administered with adjuvant glucopyranosyl lipid A-liposome Quillaja saponaria 21 formulation (GLA-LSQ) on days 1, 29, and 85 or 1 and 490 to healthy, malaria-naive adults. The primary end points were safety and reactogenicity. The secondary end points were antibody responses and Plasmodium falciparum parasitemia after homologous controlled human malaria infection. RESULTS: Participants were enrolled into 4 groups receiving rCSP/GLA-LSQ: 10 µg × 3 (n = 20), 30 µg × 3 (n = 10), 60 µg × 3 (n = 10), or 60 µg × 2 (n = 9); 10 participants received 30 µg rCSP alone × 3, and there were 6 infectivity controls. Participants experienced no serious adverse events. Rates of solicited and unsolicited adverse events were similar among groups. All 26 participants who underwent controlled human malaria infection 28 days after final vaccinations developed malaria. Increasing vaccine doses induced higher immunoglobulin G titers but did not achieve previously established RTS,S benchmarks. CONCLUSIONS: rCSP/GLA-LSQ had favorable safety results. However, tested regimens did not induce protective immunity. Further investigation could assess whether adjuvant or schedule adjustments improve efficacy. CLINICAL TRIALS REGISTRATION: NCT03589794.

Effectiveness of Recombinant Zoster Vaccine Against Herpes Zoster in a Real-World Setting.

BACKGROUND: A 2-dose series of recombinant zoster vaccine (RZV) was 97% effective against herpes zoster (HZ) in a pivotal clinical trial. OBJECTIVE: To evaluate real-world effectiveness of RZV against HZ. DESIGN: Prospective cohort study. SETTING: Four health care systems in the Vaccine Safety Datalink. PARTICIPANTS: Persons aged 50 years or older. MEASUREMENTS: The outcome was incident HZ defined by a diagnosis with an antiviral prescription. Cox regression was used to estimate the hazard of HZ in vaccinated persons compared with unvaccinated persons, with adjustment for covariates. Vaccine effectiveness (VE) was calculated as 1 minus the adjusted hazard ratio and was estimated by time since the last RZV dose and by corticosteroid use. RESULTS: The study included nearly 2.0 million persons who contributed 7.6 million person-years of follow-up. After adjustment, VE of 1 dose was 64% and VE of 2 doses was 76%. After 1 dose only, VE was 70% during the first year, 45% during the second year, 48% during the third year, and 52% after the third year. After 2 doses, VE was 79% during the first year, 75% during the second year, and 73% during the third and fourth years. Vaccine effectiveness was 65% in persons who received corticosteroids before vaccination and 77% in those who did not. LIMITATION: Herpes zoster could not be identified as accurately in these observational data as in the previous clinical trials. CONCLUSION: Two doses of RZV were highly effective, although less effective than in the previous clinical trials. Two-dose effectiveness waned very little during the 4 years of follow-up. However, 1-dose effectiveness waned substantially after 1 year, underscoring the importance of the second dose. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Comparative immunogenicity and safety of SpikoGen®, a recombinant SARS-CoV-2 spike protein vaccine in children and young adults: An immuno-bridging clinical trial.

BACKGROUND: SpikoGen® is a recombinant subunit spike protein ectodomain vaccine manufactured in insect cells and formulated with the novel polysaccharide-based Advax-CpG55.2 adjuvant. This study aimed to compare the immunogenicity and safety of SpikoGen® vaccine in children, adolescents and young adults. METHODS: This was a non-randomized, three-arm, open-label, parallel-group, immuno-bridging, non-inferiority trial to compare the immunogenicity and safety of a primary course of two intramuscular doses of SpikoGen® vaccine in children aged 5 to < 12 years, adolescents aged 12 to < 18 years and young adults aged 18 to 40 years. Children 5-12 years received a half dose of 12.5 µg spike protein, whereas the other groups received the full vaccine dose. Vaccine immunogenicity was evaluated via assessment of serum anti-spike and neutralizing antibodies 14 days after the second dose. Solicited adverse events were recorded for 7 days after each vaccination. Safety assessments including serious adverse events were continued through six months after the second dose in children and adolescents. RESULTS: Two weeks after the second dose, seroconversion rates for neutralizing antibody levels were not significantly different for children (59.50 %), adolescents (52.06 %) and adults (56.01 %). The 95 % confidence interval of the difference in seroconversion rates between children and adults was within the prespecified non-inferiority margin of 10 % (-12 % to 5 %). SpikoGen® vaccine was well tolerated in all age groups with the most common solicited adverse events being injection site pain and fatigue which were generally transient and mild. CONCLUSION: SpikoGen® vaccine was shown to be safe, well tolerated and immunogenic in children as young as 5 years of age, with non-inferior responses to those seen in adults. The Iranian FDA authorisation of SpikoGen® vaccine is now extended down to 5 years of age.