Delivery vehicle and route of administration influences self-amplifying RNA biodistribution, expression kinetics, and reactogenicity.

Self-amplifying RNA (saRNA) is a next-generation RNA platform derived from an alphavirus that enables replication in host cytosol, offering a promising shift from traditional messenger RNA (mRNA) therapies by enabling sustained protein production from minimal dosages. The approval of saRNA-based vaccines, such as the ARCT-154 for COVID-19 in Japan, underscores its potential for diverse therapeutic applications, including vaccine development, cancer immunotherapy, and gene therapy. This study investigates the role of delivery vehicle and administration route on saRNA expression kinetics and reactogenicity. Employing ionizable lipid-based nanoparticles (LNPs) and polymeric nanoparticles, we administered saRNA encoding firefly luciferase to BALB/c mice through six routes (intramuscular (IM), intradermal (ID), intraperitoneal (IP), intranasal (IN), intravenous (IV), and subcutaneous (SC)), and observed persistent saRNA expression over a month. Our findings reveal that while LNPs enable broad route applicability and stability, pABOL (poly (cystamine bisacrylamide-co-4-amino-1-butanol)) formulations significantly amplify protein expression via intramuscular delivery. Notably, the disparity between RNA biodistribution and protein expression highlight the nuanced interplay between administration routes, delivery vehicles, and therapeutic outcomes. Additionally, our research unveiled distinct biodistribution profiles and inflammatory responses contingent upon the chosen delivery formulation and route. This research illuminates the intricate dynamics governing saRNA delivery, biodistribution and reactogenicity, offering essential insights for optimizing therapeutic strategies and advancing the clinical and commercial viability of saRNA technologies.

Statistical considerations for the platform trial in COVID-19 vaccine priming and boosting.

The Platform trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, adaptive platform trial designed to generate evidence of the immunogenicity, reactogenicity, and cross-protection of different booster vaccination strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, specific for the Australian context. The PICOBOO trial randomises participants to receive one of three COVID-19 booster vaccine brands (Pfizer, Moderna, Novavax) available for use in Australia, where the vaccine brand subtypes vary over time according to the national vaccine roll out strategy, and employs a Bayesian hierarchical modelling approach to efficiently borrow information across consecutive booster doses, age groups and vaccine brand subtypes. Here, we briefly describe the PICOBOO trial structure and report the statistical considerations for the estimands, statistical models and decision making for trial adaptations. This paper should be read in conjunction with the PICOBOO Core Protocol and PICOBOO Sub-Study Protocol 1: Booster Vaccination. PICOBOO was registered on 10 February 2022 with the Australian and New Zealand Clinical Trials Registry ACTRN12622000238774.

Phase 3 Study Assessing Lot-to-lot Consistency of RSVPreF3 Vaccine and its Immune Response, Safety, and Reactogenicity When Co-administered with FLU-D-QIV.

BACKGROUND: A single-dose investigational respiratory syncytial virus (RSV) vaccine, RSV prefusion protein F3 (RSVPreF3), was co-administered with a single-dose quadrivalent influenza vaccine (FLU-D-QIV) in a phase 3, randomized, controlled, multicenter study in healthy, non-pregnant women aged 18-49 years. METHODS: The study was observer-blind to evaluate the lot-to-lot consistency of RSVPreF3, and single-blind to evaluate the immune response, safety, and reactogenicity of RSVPreF3 co-administered with FLU-D-QIV. RESULTS: A total of 1415 participants were included in the per-protocol set. There was a robust immune response at day 31 across each of the 3 RSVPreF3 vaccine lots; adjusted geometric mean concentration ratios (95% confidence interval [CI]) were 1.01 (0.91, 1.12), 0.93 (0.84, 1.03), and 0.92 (0.83, 1.02) for RSV1/RSV2, RSV1/RSV3, and RSV2/RSV3, respectively. For FLU-D-QIV co-administered with RSVPreF3, versus FLU-D-QIV alone at day 31, noninferiority was satisfied for 3 of 4 strains assessed, with the lower limit of the 95% CI for geometric mean ratio >0.67. CONCLUSIONS: Immunogenic consistency was demonstrated for 3 separate lots of RSVPreF3. Immunogenic noninferiority was demonstrated when comparing FLU-D-QIV administered alone, versus co-administered with RSVPreF3, for 3 strains of FLU-D-QIV. Co-administration was well tolerated, and both vaccines had clinically acceptable safety and reactogenicity profiles. CLINICAL TRIALS REGISTRATION: NCT05045144; EudraCT, 2021-000357-26.

This was a phase 3 study that compared antibodies against respiratory syncytial virus (or RSV for short) between women who were given 3 different production batches of RSV prefusion protein F3 (known as RSVPreF3) vaccine. The study also compared the antibodies between women who received either an RSV vaccine together with a flu vaccine (known as FLU-D-QIV), or a flu vaccine alone. The flu vaccine contained 4 different strains of flu virus. The study involved 1415 healthy, non-pregnant women aged 18­49 years. The antibodies checked after 31 days showed strong immune responses for all 3 RSV vaccine production batches, and similar immune responses between each of the 3 RSV vaccine production batches. The immune response of 3 of the 4 flu strains was not less when the flu vaccine was given together with the RSV vaccine than the immune response when flu vaccine was given alone and both vaccines were well tolerated.

Physiological Response to the COVID-19 Vaccine: Insights From a Prospective, Randomized, Single-Blinded, Crossover Trial.

BACKGROUND: Rapid development and implementation of vaccines constituted a crucial step in containing the COVID-19 pandemic. A comprehensive understanding of physiological responses to these vaccines is important to build trust in medicine. OBJECTIVE: This study aims to investigate temporal dynamics before and after COVID-19 vaccination in 4 physiological parameters as well as the duration of menstrual cycle phases. METHODS: In a prospective trial, 17,825 adults in the Netherlands wore a medical device on their wrist for up to 9 months. The device recorded their physiological signals and synchronized with a complementary smartphone app. By means of multilevel quadratic regression, we examined changes in wearable-recorded breathing rate, wrist skin temperature, heart rate, heart rate variability, and objectively assessed the duration of menstrual cycle phases in menstruating participants to assess the effects of COVID-19 vaccination. RESULTS: The recorded physiological signals demonstrated short-term increases in breathing rate and heart rate after COVID-19 vaccination followed by a prompt rebound to baseline levels likely reflecting biological mechanisms accompanying the immune response to vaccination. No sex differences were evident in the measured physiological responses. In menstruating participants, we found a 0.8% decrease in the duration of the menstrual phase following vaccination. CONCLUSIONS: The observed short-term changes suggest that COVID-19 vaccines are not associated with long-term biophysical issues. Taken together, our work provides valuable insights into continuous fluctuations of physiological responses to vaccination and highlights the importance of digital solutions in health care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-021-05241-5.

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).

Reactogenicity Differences between Adjuvanted, Protein-Based and Messenger Ribonucleic Acid (mRNA)-Based COVID-19 Vaccines.

Participants in studies investigating COVID-19 vaccines commonly report reactogenicity events, and concerns about side effects may lead to a reluctance to receive updated COVID-19 vaccinations. A real-world, post hoc analysis, observational 2019nCoV-406 study was conducted to examine reactogenicity within the first 2 days after vaccination with either a protein-based vaccine (NVX-CoV2373) or an mRNA vaccine (BNT162b2 or mRNA-1273) in individuals who previously completed a primary series. Propensity score adjustments were conducted to address potential confounding. The analysis included 1130 participants who received a booster dose of NVX-CoV2373 (n = 303) or an mRNA vaccine (n = 827) during the study period. Within the first 2 days after vaccination, solicited systemic reactogenicity events (adjusted) were reported in 60.5% of participants who received NVX-CoV2373 compared with 84.3% of participants who received an mRNA vaccine; moreover, 33.9% and 61.4%, respectively, reported ≥3 systemic reactogenicity symptoms. The adjusted mean (95% CI) number of systemic symptoms was 1.8 (1.6-2.0) and 3.2 (3.0-3.4), respectively. Local reactogenicity events (adjusted) were reported in 73.4% and 91.7% of participants who received NVX-CoV2373 and mRNA vaccines, respectively; the adjusted mean (95% CI) number of local symptoms was 1.5 (1.33-1.61) and 2.4 (2.31-2.52), respectively. These results support the use of adjuvanted, protein-based NVX-CoV2373 as an immunization option with lower reactogenicity than mRNAs.

The Relationship between Immunogenicity and Reactogenicity of Seasonal Influenza Vaccine Using Different Delivery Methods.

Vaccine immunogenicity and reactogenicity depend on recipient and vaccine characteristics. We hypothesized that healthy adults reporting higher reactogenicity from seasonal inactivated influenza vaccine (IIV) developed higher antibody titers compared with those reporting lower reactogenicity. We performed a secondary analysis of a randomized phase 1 trial of a trivalent IIV delivered by microneedle patch (MNP) or intramuscular (IM) injection. We created composite reactogenicity scores as exposure variables and used hemagglutination inhibition (HAI) titers as outcome variables. We used mixed-model analysis of variance to estimate geometric mean titers (GMTs) and titer fold change and modified Poisson generalized estimating equations to estimate risk ratios of seroprotection and seroconversion. Estimates of H3N2 GMTs were associated with the Systemic and Local scores among the IM group. Within the IM group, those with high reaction scores had lower baseline H3N2 GMTs and twice the titer fold change by day 28. Those with high Local scores had a greater probability of seroconversion. These results suggest that heightened reactogenicity to IM IIV is related to low baseline humoral immunity to an included antigen. Participants with greater reactogenicity developed greater titer fold change after 4 weeks, although the response magnitude was similar or lower compared with low-reactogenicity participants.

Randomized, Open-Label Phase 3 Study Evaluating Immunogenicity, Safety, and Reactogenicity of RSVPreF3 OA Coadministered with FLU-QIV-HD in Adults Aged ≥ 65.

INTRODUCTION: Respiratory syncytial virus (RSV) and influenza pose major disease burdens in older adults due to an aging immune system and comorbidities; seasonal overlap exists between these infections. In 2023, the RSV prefusion protein F3 older adult (RSVPreF3 OA) vaccine was first approved in the USA as a single dose for prevention of lower respiratory tract disease due to RSV in adults aged ≥ 60 years. The vaccine has since been approved in the European Union and elsewhere. RSVPreF3 OA and FLU-QIV-HD could be coadministered if immunogenicity, safety, and reactogenicity are not affected. METHODS: This open-label, randomized (1:1), controlled, phase 3 study in 1029 adults aged ≥ 65 years in the USA evaluated the immunogenicity (up to 1 month after last vaccine dose) and safety (up to 6 months after last vaccine dose) of RSVPreF3 OA coadministered with FLU-QIV-HD (co-ad group) versus FLU-QIV-HD alone followed by RSVPreF3 OA at a separate visit 1 month later (control group). Non-inferiority criterion was defined as an upper limit of the two-sided 95% confidence interval of the geometric mean titer (GMT) group ratio (control/co-ad) ≤ 1.5. Secondary endpoints included safety and reactogenicity. RESULTS: Proportions of participants across age categories between groups and proportions of male (50.4%) and female (49.6%) participants were well balanced; most participants were white (68.7%). Group GMT ratios for RSV-A neutralizing titers, hemagglutination inhibition titers for four influenza vaccine strains, and RSV-B neutralizing titers were non-inferior in the co-ad group versus the control group. No clinically meaningful differences in local or systemic solicited and unsolicited adverse events (AEs), serious AEs, and potential immune-mediated diseases were identified. The most common solicited AEs in both groups were injection-site pain and myalgia. CONCLUSION: In adults aged ≥ 65 years, coadministration of RSVPreF3 OA and FLU-QIV-HD was immunogenically non-inferior to the sequential administration of both vaccines 1 month apart, and had clinically acceptable safety and reactogenicity profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05559476.

Adults aged 65 years or older are vulnerable to infections caused by influenza and respiratory syncytial viruses, due to an aging immune system and other underlying conditions. Infections with both viruses increase during autumn and winter seasons in temperate climates. In 2023, a vaccine against respiratory syncytial virus, called RSVPreF3 OA, was first approved for use in adults aged 60 years or older in the USA; the vaccine has since also been approved in the European Union and elsewhere. Giving RSVPreF3 OA in the same vaccination visit (coadministration) with a high-dose influenza vaccine, called FLU-QIV-HD, which is given to adults aged 65 years or older, could help protect against both respiratory syncytial virus and influenza. This article reports the results of a phase 3 trial comparing coadministration of the RSVPreF3 OA and FLU-QIV-HD vaccines with sequential administration (FLU-QIV-HD followed by RSVPreF3 OA 1 month later) in 1029 adults aged 65 years or older in the USA. Proportions of participants across age categories between groups, and the proportions of male (50.4%) and female (49.6%) participants were well balanced; most participants were white (68.7%). Immune response to both the vaccines among participants in the coadministration arm was non-inferior to that in the sequential arm. Coadministration was well tolerated, with no meaningful differences in adverse reactions to the vaccines compared with sequential administration. The most common adverse reactions were pain at the injection site and muscle aches. This study supports the coadministration of RSVPreF3 OA and FLU-QIV-HD in adults aged 65 years or older.

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.

Sex and gender differences in adverse events following influenza and COVID-19 vaccination.

INTRODUCTION: Active and passive surveillance studies have found that a greater proportion of females report adverse events (AE) following receipt of either the COVID-19 or seasonal influenza vaccine compared to males. In a predominately young adult female population of healthcare workers, we sought to determine the intersection of biological sex and sociocultural gender differences in prospective active reporting of vaccine outcomes, which remains poorly characterized. METHODS: This cohort study enrolled Johns Hopkins Health System healthcare workers (HCWs) who were recruited from the mandatory annual fall 2019-2022 influenza vaccine and the fall 2022 COVID-19 bivalent vaccine campaigns. Vaccine recipients were enrolled the day of vaccination and AE surveys were administered two days post-vaccination for bivalent COVID-19 and influenza vaccine recipients. Data were collected regarding the presence of a series of solicited local and systemic AEs. Open-ended answers about participants' experiences with AEs also were collected for the COVID-19 vaccine recipients. RESULTS: Females were more likely to report local AEs after either influenza (OR = 2.28, p = 0.001) or COVID-19 (OR = 2.57, p = 0.008) vaccination compared to males, regardless of age or race. Males and females had comparable probabilities of reporting systemic AEs after either influenza (OR = 1.18, p = 0.552) or COVID-19 (OR = 0.96, p = 0.907) vaccination. Hormonal birth control use did not impact the rates of reported AEs following influenza vaccination among reproductive-aged female HCWs. Women reported more interruptions in their daily routine following COVID-19 vaccination than men and were more likely to seek out self-treatment. More women than men scheduled their COVID-19 vaccination before their days off in anticipation of AEs. CONCLUSIONS: Our findings highlight the need for sex- and gender-inclusive policies to inform more effective mandatory occupational health vaccination strategies. Further research is needed to evaluate the potential disruption of AEs on occupational responsibilities following mandated vaccination for healthcare workers, a predominately female population, and to more fully characterize the post-vaccination behavioral differences between men and women.

Research that addresses both the sex and gender differences of vaccine outcomes and behaviors is lacking. In this survey study of healthcare workers, comprised of mostly reproductive-aged females/women, we investigated biological sex (male/female) and gender (man/woman) differences in vaccine adverse events and outcomes following either influenza or bivalent COVID-19 vaccination.Regardless of age or race, females were more likely to report local (at injection site), but not systemic (whole body), adverse events than males, consistent across influenza and bivalent COVID-19 vaccine cohorts. Sex hormones are hypothesized to play a role in the differences in immune response following vaccination between males and females. We investigated if hormonal birth control use among females may be associated with differences in vaccine adverse events among the influenza vaccine cohort. However, there was no difference in the likelihood of reporting adverse events between birth control users and non-users. Based on open-ended responses to survey questions, women were found to report more interruptions to their daily routine than men following COVID-19 vaccination. Women were also more likely to seek out self-treatment with over-the-counter medication and intentionally schedule their vaccination around days off in anticipation of adverse events.With nearly 80% of healthcare jobs held by women, even higher for direct patient care positions like nursing, females/women may be disproportionately impacted by mandated annual vaccinations. Vaccinations are necessary for the prevention of disease transmission; however, our findings highlight a need for more equitable occupational vaccine strategies that consider both sex and gender differences.

Association between Reactogenicity and Immunogenicity in a Vaccinated Cohort with Two mRNA SARS-CoV-2 Vaccines at a High-Complexity Reference Hospital: A Post Hoc Analysis on Immunology Aspects of a Prospective Cohort Study.

Enhancing our comprehension of mRNA vaccines may facilitate the future design of novel vaccines aimed at augmenting immune protection while minimising reactogenic responses. Before this design is carried out, it is important to determine whether adaptive immunity correlates with the reactogenicity profile of vaccines. We studied a large cohort that was vaccinated with mRNA vaccines to answer this question. This was an observational study with real-world data. Reactogenicity data were obtained from the VigilVacCOVID study. Immunogenicity (humoral and cellular) data were retrieved from health records. One main population (n = 215) and two subpopulations were defined (subpopulation 1, n = 3563; subpopulation 2, n = 597). Sensitivity analyses were performed with subpopulations 1 and 2 to explore the consistency of results. We analysed the association of the intensity and types of adverse reactions with the development and quantity of elicited antibody titres. As an exploratory analysis in subpopulation 1, we assessed the association between reactogenicity and cellular immunogenicity. A higher incidence of fever, malaise, and myalgia including severe cases was significantly associated with the development and quantity of positive antibody titres. No significant findings were observed with cellular immunity. We observed a positive association between immunogenicity and reactogenicity. These findings can be relevant for the future development of our understanding of how mRNA vaccines function.

A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

BACKGROUND: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. OBJECTIVE: To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. METHODS: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. RESULTS: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. CONCLUSION: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Factors associated with reactogenicity to an investigational HIV vaccine regimen in HIV vaccine trials network 702.

BACKGROUND: Reactogenicity informs vaccine safety, and may influence vaccine uptake. We evaluated factors associated with reactogenicity in HVTN 702, a typical HIV vaccine efficacy trial with multiple doses and products. METHODS: HVTN 702, a phase 2b/3 double-blind placebo-controlled trial, randomized 5404 African participants aged 18-35 years without HIV to placebo, or ALVAC-HIV (vCP2438) at months 0, 1 and ALVAC-HIV (vCP2438) + Bivalent Subtype C gp120/MF59 at months 3, 6, 12 and 18. Using multivariate logistic regression, we evaluated associations between reactogenicity with clinical, sociodemographic and laboratory variables. RESULTS: More vaccine than placebo-recipients reported local symptoms (all p < 0.001), arthralgia (p = 0.008), chills (p = 0.012) and myalgia (p < 0.001). Reactogenicity was associated with female sex at birth (ORv = 2.50, ORp = 1.81, both p < 0.001) and geographic region. Amongst vaccine-recipients, each year of age was associated with 3 % increase in reactogenicity (OR = 1.03, p = 0.002). CONCLUSION: Vaccine receipt, female sex at birth, older age, and region may affect reactogenicity.

Reduction of adverse reactions and correlation between post-vaccination fever and specific antibody response across successive SARS-CoV-2 mRNA vaccinations.

Background: SARS-CoV-2 mRNA vaccination, recognized for high immunogenicity, frequently induces adverse reactions, especially fever. We previously reported a correlation between post-vaccination fever and specific antibody responses to the primary series and first booster. We herein report changes in adverse reactions and the correlation between post-vaccination fever and antibody responses across successive vaccinations, from monovalent to bivalent mRNA vaccines. Methods: This cohort study was conducted at a Japanese hospital to investigate adverse reactions to the monovalent primary, first booster, and BA.4/5 bivalent BNT162b2 vaccinations. Local and systemic reactions were reported through a self-reporting diary after each dose. The spike-specific IgG titers were measured following each vaccination. Results: Across 727 vaccinations in the vaccine series, the bivalent booster induced fewer adverse reactions than earlier doses. Fever ≥ 38.0 °C was significantly less frequent in the bivalent booster (12.3 %) compared to the primary series and monovalent booster (22.0 %, 26.2 %, p < 0.001). Reaction severity was also reduced in the bivalent booster. In the analysis of 70 participants with complete data for all doses, post-vaccination fever ≥ 38.0 °C exhibited the highest relative risk (RR) among all solicited reactions throughout the vaccine series (RR: 5.24 [95 % CI: 2.40-11.42] for monovalent and 6.24 [95 % CI: 2.14-18.15] for bivalent). The frequency of fever ≥ 38.0 °C after all doses was 8.6 % (6/70), with no fever ≥ 39.0 °C across all vaccinations. A high-grade post-vaccination fever was correlated with higher IgG titers, with multivariate analyses confirming this correlation as independent for each dose and unaffected by previous post-vaccination fever. Conclusions: The bivalent mRNA vaccine booster showed fewer and milder adverse reactions than the monovalent doses. Although vaccinees with a history of post-vaccination fever were more likely to experience fever after a subsequent dose, such recurrences were infrequent. A correlation between post-vaccination fever and increased IgG titers was identified for each vaccination, irrespective of post-vaccination fever history.

Carrier-free mRNA vaccine induces robust immunity against SARS-CoV-2 in mice and non-human primates without systemic reactogenicity.

Carrier-free naked mRNA vaccines may reduce the reactogenicity associated with delivery carriers; however, their effectiveness against infectious diseases has been suboptimal. To boost efficacy, we targeted the skin layer rich in antigen-presenting cells (APCs) and utilized a jet injector. The jet injection efficiently introduced naked mRNA into skin cells, including APCs in mice. Further analyses indicated that APCs, after taking up antigen mRNA in the skin, migrated to the lymph nodes (LNs) for antigen presentation. Additionally, the jet injection provoked localized lymphocyte infiltration in the skin, serving as a physical adjuvant for vaccination. Without a delivery carrier, our approach confined mRNA distribution to the injection site, preventing systemic mRNA leakage and associated systemic proinflammatory reactions. In mouse vaccination, the naked mRNA jet injection elicited robust antigen-specific antibody production over 6 months, along with germinal center formation in LNs and the induction of both CD4- and CD8-positive T cells. By targeting the SARS-CoV-2 spike protein, this approach provided protection against viral challenge. Furthermore, our approach generated neutralizing antibodies against SARS-CoV-2 in non-human primates at levels comparable to those observed in mice. In conclusion, our approach offers a safe and effective option for mRNA vaccines targeting infectious diseases.

Characteristics and Outcomes for Recipients of NVX-CoV2373: A Real-World Retrospective Study in Germany.

Real-world evidence supports SARS-CoV-2 vaccination strategies during the COVID-19 pandemic. This real-world retrospective study utilized the German Disease Analyzer database to characterize recipients of NVX-CoV2373 and explore vaccination outcomes. Recipients (≥12 years) of NVX-CoV2373 as a primary series or booster in Germany were vaccinated between March and December 2022. Outcomes included demographics and clinical characteristics of recipients, tolerability/reactogenicity-related events within 7 and 14 days post-vaccination, and protection from COVID-19. Overall, there were 597 recipients (mean age ~60 years) of NVX-CoV2373; 81% were vaccinated by a general practitioner, and 68% had a Standing Committee on Vaccination (STIKO) high-risk factor. The most common baseline comorbidities were chronic neurological (36%) and chronic intestinal (21%) diseases. Among recipients with metabolic disease (~11%), 65% had diabetes. Tolerability/reactogenicity-related symptoms were recorded in ~1% of recipients. There were no sick-leave notes associated with NVX-CoV2373. After 10 months (median, 7 months) of follow-up, 95% (95% CI, 93-95) of recipients were estimated to be protected from COVID-19. Outcomes were similar across the primary series, booster, and STIKO populations. Tolerability and COVID-19 protection support the use of NVX-CoV2373 as a primary/booster vaccination for all authorized populations, including high-risk.

Innate Responses to the Former COVID-19 Vaccine Candidate CVnCoV and Their Relation to Reactogenicity and Adaptive Immunogenicity.

Vaccines are highly effective at preventing severe coronavirus disease (COVID-19). With mRNA vaccines, further research is needed to understand the association between immunogenicity and reactogenicity, which is defined as the physical manifestation of an inflammatory response to a vaccination. This study analyzed the immune response and reactogenicity in humans, post immunization, to the former SARS-CoV-2 mRNA investigational vaccine CVnCoV (CV-NCOV-001 and CV-NCOV-002 clinical trials). Immunogenicity was investigated using whole-blood RNA sequencing, serum cytokine levels, and SARS-CoV-2-specific antibodies. The T cell responses in peripheral blood were assessed using intracellular cytokine staining (ICS) and high-dimensional profiling in conjunction with SARS-CoV-2 antigen-specificity testing via mass cytometry. Reactogenicity was graded after participants' first and second doses of CVnCoV using vaccine-related solicited adverse events (AEs). Finally, a Spearman correlation was performed between reactogenicity, humoral immunity, and serum cytokine levels to assess the relationship between reactogenicity and immunogenicity post CVnCoV vaccination. Our findings showed that the gene sets related to innate and inflammatory immune responses were upregulated one day post CVnCoV vaccination, while the gene sets related to adaptive immunity were upregulated predominantly one week after the second dose. The serum levels of IFNα, IFNγ, IP-10, CXCL11, IL-10, and MCP-1 increased transiently, peaking one day post vaccination. CD4+ T cells were induced in all vaccinated participants and low frequencies of CD8+ T cells were detected by ex vivo ICS. Using mass cytometry, SARS-CoV-2 spike-specific CD8+ T cells were induced and were characterized as having an activated effector memory phenotype. Overall, the results demonstrated a positive correlation between vaccine-induced systemic cytokines, reactogenicity, and adaptive immunity, highlighting the importance of the balance between the induction of innate immunity to achieve vaccine efficacy and ensuring low reactogenicity.

COVID-19 vaccine reactogenicity among participants enrolled in the GENCOV study.

BACKGROUND: GENCOV is a prospective, observational cohort study of COVID-19-positive adults. Here, we characterize and compare side effects between COVID-19 vaccines and determine whether reactogenicity is exacerbated by prior SARS-CoV-2 infection. METHODS: Participants were recruited across Ontario, Canada. Participant-reported demographic and COVID-19 vaccination data were collected using a questionnaire. Multivariable logistic regression was performed to assess whether vaccine manufacturer, type, and previous SARS-CoV-2 infection are associated with reactogenicity. RESULTS: Responses were obtained from n = 554 participants. Tiredness and localized side effects were the most common reactions across vaccine doses. For most participants, side effects occurred and subsided within 1-2 days. Recipients of Moderna mRNA and AstraZeneca vector vaccines reported reactions more frequently compared to recipients of a Pfizer-BioNTech mRNA vaccine. Previous SARS-CoV-2 infection was independently associated with developing side effects. CONCLUSIONS: We provide evidence of relatively mild and short-lived reactions reported by participants who have received approved COVID-19 vaccines.

SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase.

It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of the humoral responses to SARS-CoV-2 infection and vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing immunity mounted higher antibody responses faster and achieved higher steady-state antibody titers than naive individuals. Antibody kinetics were characterized by two phases: an initial rapid decay, followed by a stabilization phase with very slow decay. Booster vaccination equalized the differences in antibody concentration between participants with and without hybrid immunity, but the peak antibody titers decreased with each successive antigen exposure. Breakthrough infections increased antibodies to similar titers as an additional vaccine dose in naive individuals. Our study provides strong evidence that SARS-CoV-2 antibody responses are long lasting, with initial waning followed by stabilization.

Comparing reactogenicity of COVID-19 vaccine boosters: a systematic review and meta-analysis.

INTRODUCTION: Different COVID-19 vaccines are being utilized as boosters. This systematic review and meta-analysis aims to evaluate the reactogenicity of COVID-19 vaccines given as booster doses, according to vaccine type, dose, timing, participant characteristics and primary immunization regimen received. METHODS: Four databases (MEDLINE, Embase, Web of Science and CENTRAL) were searched for randomized controlled trials between 1 January 2020 and 1 January 2023 according to predetermined criteria. RESULTS: Twenty-eight studies describing 19 vaccines of four different types (viral vector, inactivated, mRNA and protein sub-unit) were identified. BNT162b2 vaccine (Pfizer-BioNTech) was selected as the control as it was most often compared with other vaccines. Fever, fatigue, headache, injection-site pain, redness, and swelling were the most frequently reported solicited events. mRNA vaccines were the most reactogenic, followed by viral vector vaccines and protein sub-unit vaccines, while inactivated vaccines were the least reactogenic. Full-dose vaccines were more reactogenic than half-dose vaccines. Heterologous BNT162b2 boosters were more reactogenic than boosters with the same vaccine used for primary immunization. CONCLUSIONS: COVID-19 vaccine booster schedules have distinct reactogenicity profiles, dependent on dose and vaccine type, which may allow targeted recommendations and provide choice for specific populations. Greater standardization of adverse event reporting will aid future studies.