Two-dose Regimen Research Articles

Immunogenicity and safety of two-dose or three-dose regimens of inactivated COVID-19 vaccines in patients with pulmonary tuberculosis: a randomised clinical trial

Immunogenicity and safety of two-dose or three-dose regimens of inactivated COVID-19 vaccines in patients with pulmonary tuberculosis: a randomised clinical trial

Immunogenicity to Herpes Zoster recombinant subunit vaccine in immune-mediated rheumatic patients under treatment with JAK inhibitors.

Patients with immune-mediated rheumatic diseases (IMRDs) face an elevated risk of varicella-zoster virus infection (VZV), and herpes zoster (HZ). Treatment with immunosuppressors further increases the risk. A new recently approved adjuvant recombinant inactive vaccine, offers safe protection against HZ. However, limited data exist on the efficacy of this new vaccine in patients with IMRDs treated with JAK inhibitors. We aimed to characterize B cell and T cell immune responses elicited by the HZ recombinant subunit vaccine in patients with IMRDs under treatment with JAK inhibitors, and to identify factors that might be associated with reduced immunogenicity, and therefore reduced protection. We investigated humoral, and cellular CD4 and CD8 immune responses following a two-dose regimen of the recombinant inactive vaccine in 43 patients with rheumatic diseases treated with different JAK inhibitors. The responses were compared with age, gender and disease-matched healthy controls. Patients with IMRDs treated with JAK inhibitors showed reduced seroconversion rate (63% vs 100% and lower VZV IgG titers (1222 ± 411 vs 3048 ± 556, p< 0.0001) as compared with healthy controls. Functional T CD4 (IL-2 plus IFN-γ secretion) and T CD8 (Granzyme A and/or Granzyme B secretion) immune responses were also significantly diminished in IMRDs patients. Negative correlation was found between VZV antibody titers and age, specific treatments (baricitinib, tofacitinib, upadacitinib), cumulative methotrexate and glucocorticoid doses, history of multiple DMARDs, and treatment duration with JAK inhibitors. Functional T-CD4 responses but not functional T-CD8 responses also showed similar negative correlations. Positive associations were observed between functional T-CD4 and T-CD8 responses. Our study provides valuable insights into the immune responses elicited by the recombinant inactive vaccine in patients with IMRDs treated with JAK inhibitors. In these patients we have observed a broad impact on the adaptive humoral and cellular immune responses, suggesting a potential reduction in protection against herpes zoster infection and VHZ reactivation.

Three-Dose Antifungal Treatment Improves the Efficacy for Severe Vulvovaginal Candidiasis

Vulvovaginal candidiasis (VVC) is a prevalent gynecological infection characterized by high incidence and recurrent episodes, causing significant distress in women. This study aims to assess the effectiveness of different clotrimazole and fluconazole treatment regimens for severe vulvovaginal candidiasis (SVVC). A retrospective analysis was conducted on 1303 cases of SVVC among first-time visitors to the gynecology outpatient department at Peking University Shenzhen Hospital between January 2013 and December 2022. Vaginal secretions were systematically collected for fungal culture, with species identification conducted using Chromogenic culture medium and API Candida test reagents. Mycological cure rates were assessed at days 7–14, days 25–35, and day 35 to 6 months after treatment. The three-dose clotrimazole regimen demonstrated significantly higher mycological cure rates (85.7%, 80.0% and 74.6% at three follow-up periods, respectively) compared to the two-dose clotrimazole regimen (76.0%, 61.6%, and 59.8%, all P < 0.05). The three-dose fluconazole regimen showed no significant difference to three-dose clotrimazole regimen, with cure rates of 82.8%, 79.3%, and 75.9% (all P > 0.05). The two-dose fluconazole regimen had cure rates of 74.3%, 56.4% and 51.1%, with no significant difference from two-dose clotrimazole regimen at days 7–14 and 25–35, but lower than three-dose fluconazole regimen at days 25–35 and 35 to 6 months. The three-dose clotrimazole regimen demonstrated higher cure rates in Candida albicans and non-albicans Candida SVVC cases than two-dose regimen. These findings suggest that three-dose antifungal regimens may be more efficacious than two-dose regimens for SVVC. The three-dose clotrimazole regimen could serve as a promising alternative for SVVC management.

Inactivated vaccine dosage and serum IgG levels correlate with persistent COVID-19 infections in hematologic malignancy patients during the Omicron Surge in China

PurposeThe essence of this scholarly work was to carefully outline the key factors intensifying the virulence and protracted contagion of COVID-19, particularly among individuals afflicted with hematologic malignancies (HM), in an epoch predominantly governed by the Omicron variant.MethodsAdults with HM diagnosed with COVID-19 from November 2022 to February 2023 were monitored in this retrospective study. Patient blood samples yielded biochemical data, and COVID-19 was confirmed through RNA or antigen testing. The factors affecting severity and infection duration were examined using both univariate and multivariate logistic regression analyses. For calculating the overall survival probabilities, the Kaplan–Meier product limit approach was employed.ResultsIn the examined cohort, 133 individuals diagnosed with HM and concomitantly infected with COVID-19 were scrutinized. Of the participants, 29.3% (39 patients) were classified as Severe/Critical, while the other 70.7% (94 patients) were categorized as Non-severe. A significant difference was observed in vaccination status: 61.7% of patients in the Non-severe group had received at least a two-dose vaccine regimen, whereas 61.5% of the Severe/Critical group had either minimal or only one dose of vaccination. The data analysis revealed that elevated C-reactive protein levels (≥ 100 mg/L) significantly raised the risk of severe/critical conditions in HM patients with COVID-19, as determined by advanced multivariate logistic regression. The odds ratio was 3.415 with a 95% confidence interval of 1.294–9.012 (p = 0.013). Patients who continued to have positive nucleic acid tests and ongoing symptoms beyond 30 days were categorized as having a persistent infection, whereas those who achieved infection control within this timeframe were categorized as having infection recovery. Of the HM cohort, 11 did not survive beyond 30 days after diagnosis. The results from a competing risk model revealed that increased interleukin-6 levels (HR: 2.626, 95% CI: 1.361–5.075; p = 0.004) was significantly associated with persistent infection. Conversely, receiving more than two vaccine doses (HR: 0.366, 95% CI: 0.158–0.846; p = 0.019), and having high IgG levels (≥ 1000 mg/dl) (HR: 0.364, 95% CI: 0.167–0.791; p = 0.011), were associated with infection recovery. There was a notable disparity in survival rates between patients with persistent infections and infection recovery, with those in the non-persistent group demonstrating superior survival outcomes (P < 0.001).ConclusionsIn conclusion, the study determined that HM patients with COVID-19 and increased C-reactive protein levels had a higher likelihood of severe health outcomes. Persistent infection tended to be more prevalent in those with vaccine dosages (< 2 doses), lower IgG levels, and higher interleukin-6 levels.

Network Analysis of Dysregulated Immune Response to COVID-19 mRNA Vaccination in Hemodialysis Patients

Introduction: End-stage renal disease (ESRD) results in immune dysfunction that is characterized by both systemic inflammation and immune incompetence, leading to impaired responses to vaccination. Methods: To unravel the complex regulatory immune interplay in ESRD, we performed the network-based transcriptomic profiling of ESRD patients on maintenance hemodialysis (HD) and matched healthy controls (HCs) who received the two-dose regimen of the COVID-19 mRNA vaccine BNT162b2. Results: Co-expression networks based on blood transcription modules (BTMs) of genes differentially expressed between the HD and HC groups revealed co-expression patterns that were highly similar between the two groups but weaker in magnitude in the HD compared to HC subjects. These networks also showed weakened coregulation between BTMs within the dendritic cell (DC) family as well as with other BTM families involved with innate immunity. The gene regulatory networks of the most enriched BTMs, likewise, highlighted weakened targeting by transcription factors of key genes implicated in DC, natural killer (NK) cell, and T cell activation and function. The computational deconvolution of immune cell populations further bolstered these findings with discrepant proportions of conventional DC subtypes, NK T cells, and CD8+ T cells in HD subjects relative to HCs. Conclusion: Altogether, our results indicate that constitutive inflammation in ESRD compromises the activation of DCs and NK cells, and, ultimately, their mediation of downstream lymphocytes, leading to a delayed but intact immune response to mRNA vaccination.

Mosquitocidal efficacy and pharmacokinetics of single-dose ivermectin versus three-day dose regimen for malaria vector control compared with albendazole and no treatment: An open-label randomized controlled trial

ObjectivesWhen malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations. However, questions remain regarding the optimal dosing. This study aimed to compare the mosquitocidal effect and pharmacokinetics of two-dose regimens of ivermectin for malaria vector control. DesignWe conducted an open-label randomized control trial in Kenya, staggered in blocks with sequential intervention groups and parallel controls. Participants were randomly assigned (2:1:1:1) using computer random-sequence generation, unstratified, with one block of six pharmacokinetics-only participants (single-dose ivermectin) and six blocks of four participants (3:1 intervention vs control), to receive single-dose ivermectin (400 mcg/kg, n = 12), three daily doses (3-day regimen 300 mcg/kg, n = 6), albendazole (400 mg, n = 6), or no treatment (negative control, n = 6). Our primary outcome was Anopheles gambiae survival (time-to-event [days]) after blood feeding up to 10 days after drug administration. We also evaluated pharmacokinetics (peak plasma and capillary blood concentration, areas under the plasma and capillary blood concentration-time curve from time of last administration to time of last observation, time to reach peak plasma and capillary blood concentration, terminal elimination half-life) up to 7 days after treatment. ResultsA total of 36 healthy volunteers aged 21-32 years were recruited into the study and followed up to completion, with two participants not attending the visit on day 28. All drug regimens were well-tolerated. Both regimens showed significant mosquitocidal effect in the first 7 days. At 10 days after treatment, the single dose presented superior longevity of effect (adjusted hazard ratio = 3.91; 95% confidence interval = 1.93-7.93; P <0.001) compared with the triple dose (adjusted hazard ratio = 1.79; 95% confidence interval = 0.88-3.62; P = 0.0.11). Albendazole had, overall, no mosquitocidal effect. ConclusionsIt is unclear why a single dose led to increased bio-efficacy compared with a triple dose. We recommend trials investigating ivermectin mass drug administrations for malaria control to consider single-dose ivermectin. A single-dose regimen is also expected to present additional operational advantages compared with a 3-day regimen, leading to improved programmatic suitability.

A two-dose regimen of Qβ virus-like particle-based vaccines elicit protective antibodies against heroin and fentanyl.

Opioid overdoses and the growing rate of opioid use disorder (OUD) are major public health concerns, particularly in the United States. Current treatment approaches for OUD have failed to slow the growth of the opioid crisis. Opioid vaccines have shown pre-clinical success in targeting multiple different opioid drugs. However, the need for many immunizations can limit their clinical implementation. In this study, we investigate the development of novel opioid vaccines by independently targeting fentanyl and the active metabolites of heroin using a bacteriophage virus-like particle (VLP) vaccine platform. We establish the successful conjugation of haptens to bacteriophage Qβ VLPs and demonstrate immunogenicity of Qβ-fentanyl, Qβ-morphine, and Qβ-6-acetylmorphine in animal models after one or two immunizations. We show that in independently or in combination, these vaccines elicit high-titer, high-avidity, and durable antibody responses. Moreover, we reveal their protective capacities against heroin or fentanyl challenge after two immunizations. Overall, these findings establish Qβ-VLP conjugated vaccines for heroin and fentanyl as very promising opioid vaccine candidates.

Neutralizing and binding antibody responses to SARS-CoV-2 with hybrid immunity in pregnancy

Hybrid immunity against SARS-CoV-2 has not been well studied in pregnancy. We conducted a comprehensive analysis of neutralizing antibodies (nAb) and binding antibodies in pregnant individuals who received mRNA vaccination, natural infection, or both. A third vaccine dose augmented nAb levels compared to the two-dose regimen or natural infection alone; this effect was more pronounced in hybrid immunity. There was reduced anti-Omicron nAb, but the maternal-fetal transfer efficiency remained comparable to that of other variants. Vaccine-induced nAbs were transferred more efficiently than infection-induced nAbs. Anti-spike receptor binding domain (RBD) IgG was associated with nAb against wild-type (Wuhan-Hu-1) following breakthrough infection. Both vaccination and infection-induced anti-RBD IgA, which was more durable than anti-nucleocapsid IgA. IgA response was attenuated in pregnancy compared to non-pregnant controls. These data provide additional evidence of augmentation of humoral immune responses in hybrid immunity in pregnancy.

An innate immune signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.

Antibody-mediated protection can depend on mechanisms varying from neutralization to Fc-dependent innate immune-cell recruitment. Adjuvanted vaccine development relies on a holistic understanding of how adjuvants modulate the quantity/titer and quality of the antibody response. A Phase 2 trial (ClinicalTrials.gov: NCT00805389) evaluated hepatitis B vaccines formulated with licensed adjuvants (AS01B, AS01E, AS03, AS04 or Alum) in antigen-naïve adults. The trial investigated the role of adjuvants in shaping antibody-effector functions, and identified an innate transcriptional response shared by AS01B, AS01E and AS03. We integrated previously reported data on the innate response (gene expression, cytokine/C-reactive protein levels) and on quantitative/qualitative features of the mature antibody response (Fc-related parameters, immunoglobulin titers, avidity). Associations between the innate and humoral parameters were explored using systems vaccinology and a machine-learning framework. A dichotomy in responses between AS01/AS03 and AS04/Alum (with the former two contributing most to the association with the humoral response) was observed across all timepoints of this longitudinal study. The consistent patterns over time suggested a similarity in the impacts of the two-dose immunization regimen, year-long interval, and non-adjuvanted antigenic challenge given one year later. An innate signature characterized by interferon pathway-related gene expression and secreted interferon-γ-induced protein 10 and C-reactive protein, which was shared by AS01 and AS03, consistently predicted both the qualitative antibody response features and the titers. The signature also predicted from the antibody response quality, the group of adjuvants from which the administered vaccine was derived. An innate signature induced by AS01- or AS03-adjuvanted vaccines predicts the antibody response magnitude and quality consistently over time.

Inactivated rabies-based Lassa fever virus vaccine candidate LASSARAB protects nonhuman primates from lethal disease

Lassa fever virus (LASV), a member of the Arenavirus family, is the etiological agent of Lassa fever, a severe hemorrhagic disease that causes considerable morbidity and mortality in the endemic areas of West Africa. LASV is a rodent-borne CDC Tier One biological threat agent and is on the World Health Organization’s (WHO) Priority Pathogen list. Currently, no FDA-licensed vaccines or specific therapeutics are available. Here, we describe the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of LASV (LASSARAB). Nonhuman primates (NHPs) were administered a two-dose regimen of LASSARAB or an irrelevant RABV-based vaccine to serve as a negative control. NHPs immunized with LASSARAB developed strong humoral responses to LASV-GPC. Upon challenge, NHPs vaccinated with LASSARAB survived to the study endpoint, whereas NHPs in the control group did not. This study demonstrates that LASSARAB is a worthy candidate for continued development.

Delivery and Safety of a Two-Dose Preventive Ebola Virus Disease Vaccine in Pregnant and Non-Pregnant Participants during an Outbreak in the Democratic Republic of the Congo.

During the 2018-2020 Ebola virus disease (EVD) outbreak, residents in Goma, Democratic Republic of the Congo, were offered a two-dose prophylactic EVD vaccine. This was the first study to evaluate the safety of this vaccine in pregnant women. Adults, including pregnant women, and children aged ≥1 year old were offered the Ad26.ZEBOV (day 0; dose 1), MVA-BN-Filo (day 56; dose 2) EVD vaccine through an open-label clinical trial. In total, 20,408 participants, including 6635 (32.5%) children, received dose 1. Fewer than 1% of non-pregnant participants experienced a serious adverse event (SAE) following dose 1; one SAE was possibly related to the Ad26.ZEBOV vaccine. Of the 1221 pregnant women, 371 (30.4%) experienced an SAE, with caesarean section being the most common event. No SAEs in pregnant women were considered related to vaccination. Of 1169 pregnancies with a known outcome, 55 (4.7%) ended in a miscarriage, and 30 (2.6%) in a stillbirth. Eleven (1.0%) live births ended in early neonatal death, and five (0.4%) had a congenital abnormality. Overall, 188/891 (21.1%) were preterm births and 79/1032 (7.6%) had low birth weight. The uptake of the two-dose regimen was high: 15,328/20,408 (75.1%). The vaccine regimen was well-tolerated among the study participants, including pregnant women, although further data, ideally from controlled trials, are needed in this crucial group.

Immunogenicity of an Extended Dose Interval for the Ad26.ZEBOV, MVA-BN-Filo Ebola Vaccine Regimen in Adults and Children in the Democratic Republic of the Congo.

During the 2018-2020 Ebola virus disease outbreak in Democratic Republic of the Congo, a phase 3 trial of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine (DRC-EB-001) commenced in Goma, with participants being offered the two-dose regimen given 56 days apart. Suspension of trial activities in 2020 due to the COVID-19 pandemic led to some participants receiving a late dose 2 outside the planned interval. Blood samples were collected from adults, adolescents, and children prior to their delayed dose 2 vaccination and 21 days after, and tested for IgG binding antibodies against Ebola virus glycoprotein using the Filovirus Animal Nonclinical Group (FANG) ELISA. Results from 133 participants showed a median two-dose interval of 9.3 months. The pre-dose 2 antibody geometric mean concentration (GMC) was 217 ELISA Units (EU)/mL (95% CI 157; 301) in adults, 378 EU/mL (281; 510) in adolescents, and 558 EU/mL (471; 661) in children. At 21 days post-dose 2, the GMC increased to 22,194 EU/mL (16,726; 29,449) in adults, 37,896 EU/mL (29,985; 47,893) in adolescents, and 34,652 EU/mL (27,906; 43,028) in children. Participants receiving a delayed dose 2 had a higher GMC at 21 days post-dose 2 than those who received a standard 56-day regimen in other African trials, but similar to those who received the regimen with an extended interval.

A cost benefit analysis of varicella vaccination in South Korea

BackgroundThe introduction of varicella vaccination has significantly reduced the burden of chickenpox in many countries, but outbreaks still occur in populations with high vaccination coverage. To address this, some countries, including the United States, Germany, and Japan, have adopted a two-dose varicella vaccination recommendation. Economic evaluations are crucial for assessing vaccine recommendations; however, there are limited studies exist in Asian countries. Thus, our study aimed to evaluate the cost-benefit of one-dose and two-dose varicella vaccination programs compared to no vaccination in South Korea, incorporating updated data on disease burden and costs. MethodsWe utilized data from South Korea’s health databases to estimate varicella burden and vaccination records. Decision tree analysis was employed to compare costs and benefits of vaccination strategies over a ten-year period for the 2012 birth cohort. Sensitivity analyses were conducted to assess the impact of various variables. ResultsBoth one-dose and two-dose vaccination programs showed cost-benefit compared to no vaccination, with substantial societal cost savings. The one-dose program yielded a benefit-cost ratio (BCR) of1.43, while the two-dose program had a direct BCR of1.28. Sensitivity analyses confirmed the robustness of these findings. ConclusionOur study demonstrates the economic benefits of varicella vaccination in South Korea, aligning with findings from other countries. While the second dose did not show additional cost savings compared to the one-dose program, other factors like disease severity and transmission dynamics should be considered. Implementing either a one-dose or two-dose varicella vaccination regimen in South Korea could lead to cost reductions and improved cost-effectiveness compared to no vaccination, emphasizing the importance of vaccination programs in reducing disease burden and enhancing public health outcomes.

Effectiveness of two-dose vs. one-dose varicella vaccine in children in Shanghai, China: a prospective cohort study.

Varicella, a highly contagious viral disease caused by the varicella-zoster virus (VZV), affects millions globally, with a higher prevalence among children. After the initial infection, VZV lies dormant in sensory ganglia and has the potential to reactivate much later, causing herpes zoster (HZ). Vaccination is one of the most effective methods to prevent varicella, and the two-dose varicella vaccine (VarV) regimen is widely used around the world. In China, the VarV has been included in the national immunization programme with a recommended single-dose regimen. This study aimed to compare the effectiveness of the two-dose vs. one-dose VarV regimen in children in Shanghai, China. A prospective cohort study was conducted in Shanghai, China, from September 2018 to December 2022. The study enrolled children aged 3-18 years who had received either the one-dose, two-dose, or 0-dose VarV regimen. Vaccination history, varicella infection status, and relevant variables, including demographic information (name, date of birth and sex) and medical history (clinical features of varicella and illness duration) were collected through medical record review and parental interviews. A total of 3,838 children were included in the study, with 407 in the 0-dose regimen group, 2,107 in the one-dose regimen group and 1,324 in the two-dose regimen group. The corresponding incidence density in these groups was 0.13, 0.05 and 0.03 cases per 1,000 person-days, respectively. The adjusted vaccine effectiveness (VE) was 81.7% (95%CI: 59.3-91.8%) for the two-dose regimen and 60.3% (95%CI: 29.3-77.7%) for the one-dose regimen, compared to the 0-dose regimen. The two-dose VarV regimen showed a protective effectiveness of 47.6% (95%CI: 2.5-71.9%) compared to the one-dose VarV regimen. This study provides evidence supporting the greater effectiveness of the two-dose VarV regimen in preventing varicella infection compared to the one-dose regimen.

USE OF MISOPROSTOL IN ABORTION ON MEDICAL GROUNDS – OUR CLINICAL EXPERIENCE

Purpose. In clinical practice in hospital conditions, the preferred choice of behavior regarding fetal anomalies is to perform a medical abortion after the opinion of a specialized committee in the hospital. There are no observations conducted by other authors on abortions related to termination of pregnancy for medical reasons at a different time. The team conducts its observation in hospital conditions. Material/Methods: Conducted own retrospective study for the period January 2021 – February 2024 with the participation of 45 patients who went through a pregnancy termination committee on medical grounds. All women who passed through the committee for medically indicated abortion, in which fetal anomalies incompatible with life or severely debilitating were found, were examined. Women are at different stages of pregnancy, age, education, number of pregnancies and births, concomitant diseases, a type of test to diagnose abnormalities in the fetus (invasive and non-invasive). The type of abnormality that is the cause of an abortion on medical grounds has also been investigated. The dosage applied is- 1st tablet of 400 mg Misoprostol per vagine, second and third tablets in 3 hours sub buccal, the maximum dose is 5 tablets in 24 hours or 2000 microgram Misoprostol. Results. For 88,9% of the cases, they have a positive opinion of the commission in the hospital structure, and 11,1% have a refusal. Group matching of patients was performed by education and whether they had good outpatient follow-up, regardless of the duration of pregnancy. Patients with higher education had better outpatient follow-up (χ2=15.497, p=0.000) than those with secondary and primary education. There was a significant association between the dosing regimen and pregnancy severity; the relationship between the two-dose regimen was significant (χ2=53.862, p=0.000), and the three-dose regimen was highly successful in 73.3% of cases. Conclusion. The correct choice of method of application of the therapeutic regimen requires preliminary and detailed medical preparation of the patient and good clinical experience of the treating doctor. The applied therapeutic approach reduces the risk to the patient and has a rapid recovery period. Early and timely diagnosis has an important informative value.

Serologic responses to the MVA-based JYNNEOS mpox vaccine in a cohort of participants from the District of Columbia (D.C.)

We assessed early antibody responses after two doses of JYNNEOS (IMVANEX) mpox vaccine in the District of Columbia (D.C.) in persons at high risk for mpox without characteristic lesions or rash. Participants with PCR mpox negative specimens (oral swab, blood, and/or rectal swab) on the day of receipt of the first vaccine dose and who provided a baseline (day 0) serum sample and at least one serum sample at ∼28, ∼42–56 days, or 180 days post vaccination were included in this analysis. Orthopoxvirus (OPXV)-specific IgG and IgM ELISAs and neutralizing antibody titers were performed, and longitudinal serologic responses were examined. Based on participants’ IgG and IgM antibody levels at baseline, they were categorized as naïve or non-naïve. Linear mixed effects regression models were conducted to determine if IgG antibody response over time varied by age, sex, HIV status, and route of administration for both naïve and non-naïve participants. Among both naïve and non-naïve participants IgG seropositivity rates increased until day 42–56, with 89.4 % of naïve and 92.1 % of non-naïve participants having detectable IgG antibodies. The proportion of naive participants with detectable IgG antibodies declined by day 180 (67.7 %) but remained high among non-naïve participants (94.4 %). Neutralizing antibody titers displayed a similar pattern, increasing initially post vaccination but declining by day 180 among naïve participants. There were no significant serologic response differences by age, sex, or HIV status. Serologic response did vary by route of vaccine administration, with those receiving a combination of intradermal and subcutaneous doses displaying significantly higher IgG values than those receiving both doses intradermally. These analyses provide initial insights into the immunogenicity of a two-dose JYNNEOS PEP regimen in individuals at high risk of mpox exposure in the United States.

Mucosal adjuvanticity and mucosal booster effect of colibactin-depleted probiotic Escherichia coli membrane vesicles

ABSTRACT There is a growing interest in development of novel vaccines against respiratory tract infections, due to COVID-19 pandemic. Here, we examined mucosal adjuvanticity and the mucosal booster effect of membrane vesicles (MVs) of a novel probiotic E. coli derivative lacking both flagella and potentially carcinogenic colibactin (ΔflhDΔclbP). ΔflhDΔclbP-derived MVs showed rather strong mucosal adjuvanticity as compared to those of a single flagellar mutant strain (ΔflhD-MVs). In addition, glycoengineered ΔflhDΔclbP-MVs displaying serotype-14 pneumococcal capsular polysaccharide (CPS14+MVs) were well-characterized based on biological and physicochemical parameters. Subcutaneous (SC) and intranasal (IN) booster effects of CPS14+MVs on systemic and mucosal immunity were evaluated in mice that have already been subcutaneously prime-immunized with the same MVs. With a two-dose regimen, an IN boost (SC-IN) elicited stronger IgA responses than homologous prime-boost immunization (SC-SC). With a three-dose regimen, serum IgG levels were comparable among all tested regimens. Homologous immunization (SC-SC-SC) elicited the highest IgM responses among all regimens tested, whereas SC-SC-SC failed to elicit IgA responses in blood and saliva. Furthermore, serum IgA and salivary SIgA levels were increased with an increased number of IN doses administrated. Notably, SC-IN-IN induced not only robust IgG response, but also the highest IgA response in both serum and saliva among the groups. The present findings suggest the potential of a heterologous three-dose administration for building both systemic and mucosal immunity, e.g. an SC-IN-IN vaccine regimen could be beneficial. Another important observation was abundant packaging of colibactin in MVs, suggesting increased applicability of ΔflhDΔclbP-MVs in the context of vaccine safety.

Safety and immunogenicity of the Euvichol-S oral cholera vaccine for prevention of Vibrio cholerae O1 infection in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial

In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. The Bill & Melinda Gates Foundation. For the Nepali translation of the abstract see Supplementary Materials section.

Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccine regimen plus Ad26.ZEBOV booster at 1 year versus 2 years in health-care and front-line workers in the Democratic Republic of the Congo: secondary and exploratory outcomes of an open-label, randomised, phase 2 trial

Health-care providers and front-line workers are at risk of contracting Ebola virus disease during an Ebola virus outbreak and consequently of becoming drivers of the disease. We aimed to assess the long-term immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen and the safety of and immune memory response to an Ad26.ZEBOV booster vaccination at 1 year or 2 years after the first dose in this at-risk population. This open-label, single-centre, randomised, phase 2 trial was conducted at one study site within a hospital in Boende, Democratic Republic of the Congo. Adult health-care providers and front-line workers, excluding those with a known history of Ebola virus disease, were vaccinated with a two-dose heterologous regimen administered at a 56-day interval via a 0·5 mL intramuscular injection in the deltoid muscle, comprising Ad26.ZEBOV as the first dose and MVA-BN-Filo as the second dose. After the initial vaccination on day 1, participants were randomly assigned (1:1) via randomisation envelopes, opened in a sequential order, to receive an Ad26.ZEBOV booster vaccination at 1 year (group 1) or 2 years (group 2) after the first dose. We present the secondary and exploratory objectives of the trial-results of the primary objective have been published elsewhere. We measured immunogenicity at six timepoints per group as geometric mean concentrations (GMCs) of Ebola virus glycoprotein-specific IgG binding antibodies, using the Filovirus Animal Non-Clinical Group ELISA. We assessed serious adverse events occurring up to 6 months after the last dose and local and systemic solicited and unsolicited adverse events reported for 7 days after the booster vaccination. Antibody responses were analysed per protocol, serious adverse events per full analysis set (FAS), and adverse events for all boosted FAS participants. This trial is registered as completed on ClinicalTrials.gov (NCT04186000). Between Dec 18, 2019, and Feb 8, 2020, 699 health-care providers and front-line workers were enrolled and 698 were randomly assigned (350 to group 1 and 348 to group 2 [FAS]); 534 (77%) participants were male and 164 (23%) were female. 319 in group 1 and 317 in group 2 received the booster. 29 (8%) in group 1 and 26 (7%) in group 2 did not complete the study, mostly due to loss to follow-up or moving out of the study area. In both groups, injection-site pain or tenderness (87 [27%] of 319 group 1 participants vs 90 [28%] of 317 group 2 participants) and headache (91 [29%] vs 93 [29%]) were the most common solicited adverse events related to the investigational product. One participant (in group 2) had a related serious adverse event after booster vaccination (fever of ≥40·0°C). Before booster vaccination, Ebola virus glycoprotein-specific IgG binding antibody GMCs were 279·9 ELISA units (EU) per mL (95% CI 250·6-312·7) in 314 group 1 participants (1 year after first dose) and 274·6 EU/mL (242·1-311·5) in 310 group 2 participants (2 years after first dose). These values were 5·2 times higher in group 1 and 4·9 times higher in group 2 than before vaccination on day 1. 7 days after booster vaccination, these values increased to 10 781·6 EU/mL (9354·4-12 426·4) for group 1 and 10 746·9 EU/mL (9208·7-12 542·0) for group 2, which were approximately 39 times higher than before booster vaccination in both groups. 1 year after booster vaccination in 299 group 1 participants, a GMC that was 7·6-times higher than before booster vaccination was still observed (2133·1 EU/mL [1827·7-2489·7]). Overall, the vaccine regimen and booster dose were well tolerated. A similar and robust humoral immune response was observed for participants boosted 1 year and 2 years after the first dose, supporting the use of the regimen and flexibility of booster dose administration for prophylactic vaccination in at-risk populations. Innovative Medicines Initiative 2 Joint Undertaking and Coalition for Epidemic Preparedness Innovations.

Lot-to-lot consistency, immunogenicity, and safety of the Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen: A phase 3, randomized, double-blind, placebo-controlled trial

ABSTRACT This phase-3, double-blind, placebo-controlled study (NCT04228783) evaluated lot-to-lot consistency of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Participants were randomized (6:6:6:1) to receive the two-dose regimen from three consecutively manufactured lots of Ad26.ZEBOV on Day 1 paired with three consecutively manufactured lots of MVA-BN-Filo on Day 57 (Groups 1–3) or two doses of placebo (Group 4). An additional cohort also received an Ad26.ZEBOV booster or placebo 4 months post-dose 2. Equivalence of the immunogenicity at 21 days post-dose 2 between any two groups was demonstrated if the 95% confidence interval (CI) of the Ebola virus glycoprotein (EBOV GP)–binding antibody geometric mean concentration (GMC) ratio was entirely within the prespecified margin of 0.5–2.0. Lot-to-lot consistency (i.e., consecutive lots can be consistently manufactured) was accomplished if equivalence was shown for all three pairwise comparisons. Results showed that the primary objective in the per-protocol immunogenicity subset (n = 549) was established for each pairwise comparison (Group 1 vs 2: GMC ratio = 0.9 [95% CI: 0.8, 1.1], Group 1 vs 3: 0.9 [0.8, 1.1], Group 2 vs 3: 1.0 [0.9, 1.2]). Equivalence of the three groups for the Ad26.ZEBOV component only was also demonstrated at 56 days post-dose 1. EBOV GP–binding antibody responses (post-vaccination concentrations >2.5-fold from baseline) were observed in 419/421 (99.5%) vaccine recipients at 21 days post-dose 2 and 445/460 (96.7%) at 56 days post-dose 1. In the booster cohort (n = 39), GMCs increased 9.0- and 11.8-fold at 7 and 21 days post-booster, respectively, versus pre-booster. Ad26.ZEBOV, MVA-BN-Filo was well tolerated, and no safety issues were identified.