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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: The LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period.
UNASSIGNED: ClinicalTrials.gov, identifier NCT05745545.

BACKGROUND: Hybrid immunity to SARS-CoV-2, resulting from both vaccination and natural infection, remains insufficiently understood in paediatric populations, despite increasing rates of breakthrough infections among vaccinated children.
METHODS: We conducted a prospective longitudinal study to investigate the magnitude, specificity, and cytokine profile of antigen-specific T cell responses elicited by breakthrough SARS-CoV-2 infection in a cohort of mRNA-vaccinated children (n = 29) aged 5-11. This longitudinal analysis involved six distinct time points spanning a 16-month period post-vaccination, during which we analysed a total of 159 blood samples. All children who were followed for at least 12 months (n = 26) experienced a breakthrough infection. We conducted cytokine release assays using minimal blood samples, and we verified the cellular origin of these responses through intracellular cytokine staining.
RESULTS: After breakthrough infection, children who had received mRNA vaccines showed enhanced Th1 responses specific to Spike peptides. Additionally, their Spike-specific T cells exhibited a distinctive enrichment of CD4+ IFN-γ+IL10+ cells, a characteristic akin to adults with hybrid immunity. Importantly, vaccination did not impede the development of multi-specific T cell responses targeting Membrane, Nucleoprotein, and ORF3a/7/8 antigens.
CONCLUSIONS: Children, previously primed with a Spike-based mRNA vaccine and experiencing either symptomatic or asymptomatic breakthrough infection, retained the ability to enhance and diversify Th1/IL-10 antigen-specific T cell responses against multiple SARS-CoV-2 proteins. These findings mirror characteristics associated with hybrid cellular immunity in adults, known to confer resistance against severe COVID-19.
BACKGROUND: This study was funded by the National Medical Research Council (NMRC) Singapore (COVID19RF-0019, MOH-000019, MOH-000535, OFLCG19May-0034 and MOH-OFYIRG19nov-0002).

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.

BACKGROUND: In recent years, infectious diseases like COVID-19 have had profound global socio-economic impacts. mRNA vaccines have gained prominence due to their rapid development, industrial adaptability, simplicity, and responsiveness to new variants. Notably, the 2023 Nobel Prize in Physiology or Medicine recognized significant contributions to mRNA vaccine research.
METHODS: Our study employed a comprehensive bibliometric analysis using the Web of Science Core Collection (WoSCC) database, encompassing 5,512 papers on mRNA vaccines from 2003 to 2023. We generated cooperation maps, co-citation analyses, and keyword clustering to evaluate the field\'s developmental history and achievements.
RESULTS: The analysis yielded knowledge maps highlighting countries/institutions, influential authors, frequently published and highly cited journals, and seminal references. Ongoing research hotspots encompass immune responses, stability enhancement, applications in cancer prevention and treatment, and combating infectious diseases using mRNA technology.
CONCLUSIONS: mRNA vaccines represent a transformative development in infectious disease prevention. This study provides insights into the field\'s growth and identifies key research priorities, facilitating advancements in vaccine technology and addressing future challenges.

Kidney transplant recipients (KTRs), like other solid organ transplant recipients display a suboptimal response to mRNA vaccines, with only about half achieving seroconversion after two doses. However, the effectiveness of a booster dose, particularly in generating neutralizing antibodies (NAbs), remains poorly understood, as most studies have mainly focused on non-neutralizing antibodies. Here, we have longitudinally assessed the humoral response to the SARS-CoV-2 mRNA vaccine in 40 KTRs over a year, examining changes in both anti-spike IgG and NAbs following a booster dose administered about 5 months post-second dose. We found a significant humoral response increase 5 months post-booster, a stark contrast to the attenuated response observed after the second dose. Of note, nearly a quarter of participants did not achieve protective plasma levels even after the booster dose. We also found that the higher estimated glomerular filtration rate (eGFR) correlated with a more robust humoral response postvaccination. Altogether, these findings underscore the effectiveness of the booster dose in enhancing durable humoral immunity in KTRs, as evidenced by the protective level of NAbs found in 65% of the patients 5 months post- booster, especially those with higher eGFR rates.

The recurrent COVID-19 infection, despite global vaccination, highlights the need for booster doses. A heterologous booster has been suggested to enhance immunity and protection against emerging variants of concern of the SARS-CoV-2 virus. In this report, we aimed to assess the safety, and immunogenicity of COReNAPCIN, as a fourth booster dose after three doses of inactivated vaccines.
METHODS: The study was conducted as a double-blind, randomized, placebo-controlled phase 1 clinical trial of the mRNA-based vaccine candidate, COReNAPCIN. The vaccine was injected as a heterologous booster in healthy Iranian adults aged 18-50 who had previously received three doses of inactivated SARS-CoV-2 vaccines. In the study, 30 participants were randomly assigned to receive either COReNAPCIN in two different doses (25 µg and 50 µg) or placebo. The vaccine candidate contained mRNA encoding the complete sequence of the pre-fusion stabilized Spike protein of SARS-CoV-2, formulated within lipid nanoparticles. The primary endpoint was safety and the secondary objective was humoral immunogenicity until 6 months post-vaccination. The cellular immunogenicity was pursued as an exploratory outcome.
RESULTS: COReNAPCIN was well tolerated in vaccinated individuals in both doses with no life-threatening or other serious adverse events. The most noticeable solicited adverse events were pain at the site of injection, fatigue and myalgia. Regarding the immunogenicity, despite the seroprevalence of SARS-CoV-2 antibodies due to the vaccination history for all and previous SARS-CoV-2 infection for some participants, the recipients of 25 and 50 µg COReNAPCIN, two weeks post-vaccination, showed 6·6 and 8·1 fold increase in the level of anti-RBD, and 11·5 and 21·7 fold increase in the level of anti-spike antibody, respectively. The geometric mean virus neutralizing titers reached 10.2 fold in the 25 µg group and 8.4 fold in 50 µg group of pre-boost levels. After 6 months, the measured anti-spike antibody concentration still maintains a geometric mean fold rise of 2.8 and 6.3, comparing the baseline levels in 25 and 50 µg groups, respectively. Additionally, the significant increase in the spike-specific IFN-ϒ T-cell response upon vaccination underscores the activation of cellular immunity.
CONCLUSIONS: COReNAPCIN booster showed favorable safety, tolerability, and immunogenicity profile, supporting its further clinical development (Trial registration: IRCT20230131057293N1).

Although previous studies have shown no increased mortality risk after the primary series of COVID-19 mRNA vaccines, reports on booster doses are lacking. This study aimed to evaluate mortality risk after the mRNA vaccine boosters in addition to the primary series. This nested case-control study included two age-specific cohorts (18-64 and ≥65 years as of February 1, 2021) in two municipalities. All deaths were identified and matched five controls for each case at each date of death (index date) with risk set sampling according to municipality, age, and sex. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for mRNA vaccines (first to fifth doses) were estimated by comparing with no vaccination within 21 and 42 days before the index date using a conditional logistic regression model. The 18-64-years cohort comprised 431 cases (mean age, 57.0 years; men, 58.2%) and 2,155 controls (mean age, 56.0; men, 58.2%), whereas the ≥65-years cohort comprised 12,166 cases (84.0; 50.2%) and 60,830 controls (84.0, 50.2%). The aORs (95% CI) in 0-21 days after the third and fourth doses in the 18-64-years cohort were 0.62 (0.24, 1.62) and 0.38 (0.08, 1.84), respectively. The aORs (95% CI) after the third to fifth doses in the ≥65 years cohort were 0.36 (0.31, 0.43), 0.30 (0.25, 0.37), and 0.26 (0.20, 0.33), respectively. In conclusion, booster doses of mRNA vaccines do not increase mortality risk. These findings could help subsequent vaccine campaigns and alleviate vaccine hesitancy.

BACKGROUND: Although there are some data regarding the COVID-19 vaccine and in in vitro fertilization (IVF) treatments, its potential impact in terms of serum immunoglobulin G (IgG) levels has not been evaluated prospectively. This study aimed to assess the effect of COVID-19 vaccine and IgG levels on IVF outcomes.
METHODS: This observational, cohort study was conducted at a referral IVF unit. Couples undergoing IVF treatment during the COVID-19 vaccination period were recruited from March-April 2021. The study compared 38 women who had received the Pfizer mRNA COVID-19 vaccination to 10 women who had not and were not infected by the virus. We also compared pre- and post-vaccination IVF treatments for 24 women. The relation between serologic titers and IVF treatment outcomes was also assessed.
RESULTS: No significant difference was found between the vaccinated and unvaccinated/uninfected groups regarding the main outcome measures. However, there was a trend toward a higher pregnancy rate for the unvaccinated group (57% vs. 23%, p = 0.078) but no difference in delivery rate (p = 0.236), gestational week (p = 0.537) or birth rate (p = 0.671).
CONCLUSIONS: We cautiously state that the COVID-19 mRNA vaccine does not affect fertility outcomes, including fertilization, pregnancy and delivery rates, obstetric outcomes, and semen parameters, regardless of measured IgG levels.

Here we conducted a multicenter open-label, randomized phase 2 and 3 study to assess the safety and immunogenicity of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-specific (BA.1/B.1.1.529), monovalent, thermostable, self-amplifying mRNA vaccine, GEMCOVAC-OM, when administered intradermally as a booster in healthy adults who had received two doses of BBV152 or ChAdOx1 nCoV-19. GEMCOVAC-OM was well tolerated with no related serious adverse events in both phase 2 and phase 3. In phase 2, the safety and immunogenicity of GEMCOVAC-OM was compared with our prototype mRNA vaccine GEMCOVAC-19 (D614G variant-specific) in 140 participants. At day 29 after vaccination, there was a significant rise in anti-spike (BA.1) IgG antibodies with GEMCOVAC-OM (P < 0.0001) and GEMCOVAC-19 (P < 0.0001). However, the IgG titers (primary endpoint) and seroconversion were higher with GEMCOVAC-OM (P < 0.0001). In phase 3, GEMCOVAC-OM was compared with ChAdOx1 nCoV-19 in 3,140 participants (safety cohort), which included an immunogenicity cohort of 420 participants. At day 29, neutralizing antibody titers against the BA.1 variant of SARS-CoV-2 were significantly higher than baseline in the GEMCOVAC-OM arm (P < 0.0001), but not in the ChAdOx1 nCoV-19 arm (P = 0.1490). GEMCOVAC-OM was noninferior (primary endpoint) and superior to ChAdOx1 nCoV-19 in terms of neutralizing antibody titers and seroconversion rate (lower bound 95% confidence interval of least square geometric mean ratio >1 and difference in seroconversion >0% for superiority). At day 29, anti-spike IgG antibodies and seroconversion (secondary endpoints) were significantly higher with GEMCOVAC-OM (P < 0.0001). These results demonstrate that GEMCOVAC-OM is safe and boosts immune responses against the B.1.1.529 variant. Clinical Trial Registry India identifier: CTRI/2022/10/046475 .