Humoral and cellular immune memory to four COVID-19 vaccines.

Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S, and Novavax NVX-CoV2373 were examined longitudinally for 6 months 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though only detectable in 60-67% of subjects at 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in antibodies, while memory T and B cells were comparatively stable. These results may also be relevant for insights against other pathogens.

Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

Strategy to develop broadly effective multivalent COVID-19 vaccines against emerging variants based on Ad5/35 platform.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron strain has evolved into highly divergent variants with several sub-lineages. These newly emerging variants threaten the efficacy of available COVID-19 vaccines. To mitigate the occurrence of breakthrough infections and re-infections, and more importantly, to reduce the disease burden, it is essential to develop a strategy for producing updated multivalent vaccines that can provide broad neutralization against both currently circulating and emerging variants. We developed bivalent vaccine AdCLD-CoV19-1 BA.5/BA.2.75 and trivalent vaccines AdCLD-CoV19-1 XBB/BN.1/BQ.1.1 and AdCLD-CoV19-1 XBB.1.5/BN.1/BQ.1.1 using an Ad5/35 platform-based non-replicating recombinant adenoviral vector. We compared immune responses elicited by the monovalent and multivalent vaccines in mice and macaques. We found that the BA.5/BA.2.75 bivalent and the XBB/BN.1/BQ.1.1 and XBB.1.5/BN.1/BQ.1.1 trivalent vaccines exhibited improved cross-neutralization ability compared to their respective monovalent vaccines. These data suggest that the developed multivalent vaccines enhance immunity against circulating Omicron subvariants and effectively elicit neutralizing antibodies across a broad spectrum of SARS-CoV-2 variants.

Mortality risk information and health-seeking behavior during an epidemic.

In a context where pessimistic survival perceptions have been widespread as a result of the HIV/AIDS epidemic (Fig. 1 A), we study vaccine uptake and other health behaviors during the recent COVID-19 pandemic. Leveraging a longitudinal cohort study in rural Malawi that has been followed for up to 25 y, we document that a 2017 mortality risk information intervention designed to reduce pessimistic mortality perceptions (Fig. 1 B) resulted in improved health behavior, including COVID-19 vaccine uptake (Fig. 1 C). We also report indirect effects for siblings and household members. This was likely the result of a reinforcing process where the intervention triggered engagement with the healthcare system and stronger beliefs in the efficacy of modern biomedical treatments, which led to the adoption of health risk reduction behavior, including vaccine uptake. Our findings suggest that health information interventions focused on survival perceptions can be useful in promoting health behavior and participation in the formal healthcare system, even during health crises-such as the COVID-19 pandemic-that are unanticipated at the time of the intervention. We also note the importance of the intervention design, where establishing rapport, tailoring the content to the local context, and spending time with respondents to convey the information contributed to the salience of the message.

Digital public health interventions at scale: The impact of social media advertising on beliefs and outcomes related to COVID vaccines.

Public health organizations increasingly use social media advertising campaigns in pursuit of public health goals. In this paper, we evaluate the impact of about $40 million of social media advertisements that were run and experimentally tested on Facebook and Instagram, aimed at increasing COVID-19 vaccination rates in the first year of the vaccine roll-out. The 819 randomized experiments in our sample were run by 174 different public health organizations and collectively reached 2.1 billion individuals in 15 languages. We find that these campaigns are, on average, effective at influencing self-reported beliefs-shifting opinions close to 1% at baseline with a cost per influenced person of about $3.41. Combining this result with an estimate of the relationship between survey outcomes and vaccination rates derived from observational data yields an estimated cost per additional vaccination of about $5.68. There is further evidence that campaigns are especially effective at influencing users' knowledge of how to get vaccines. Our results represent, to the best of our knowledge, the largest set of online public health interventions analyzed to date.

Infectious virus shedding duration reflects secretory IgA antibody response latency after SARS-CoV-2 infection.

Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.

A measles-vectored vaccine candidate expressing prefusion-stabilized SARS-CoV-2 spike protein brought to phase I/II clinical trials: candidate selection in a preclinical murine model.

In the early COVID-19 pandemic with urgent need for countermeasures, we aimed at developing a replicating viral vaccine using the highly efficacious measles vaccine as vector, a promising technology with prior clinical proof of concept. Building on our successful pre-clinical development of a measles virus (MV)-based vaccine candidate against the related SARS-CoV, we evaluated several recombinant MV expressing codon-optimized SARS-CoV-2 spike glycoprotein. Candidate V591 expressing a prefusion-stabilized spike through introduction of two proline residues in HR1 hinge loop, together with deleted S1/S2 furin cleavage site and additional inactivation of the endoplasmic reticulum retrieval signal, was the most potent in eliciting neutralizing antibodies in mice. After single immunization, V591 induced similar neutralization titers as observed in sera of convalescent patients. The cellular immune response was confirmed to be Th1 skewed. V591 conferred long-lasting protection against SARS-CoV-2 challenge in a murine model with marked decrease in viral RNA load, absence of detectable infectious virus loads, and reduced lesions in the lungs. V591 was furthermore efficacious in an established non-human primate model of disease (see companion article [S. Nambulli, N. Escriou, L. J. Rennick, M. J. Demers, N. L. Tilston-Lunel et al., J Virol 98:e01762-23, 2024, https://doi.org/10.1128/jvi.01762-23]). Thus, V591 was taken forward into phase I/II clinical trials in August 2020. Unexpected low immunogenicity in humans (O. Launay, C. Artaud, M. Lachâtre, M. Ait-Ahmed, J. Klein et al., eBioMedicine 75:103810, 2022, https://doi.org/10.1016/j.ebiom.2021.103810) revealed that the underlying mechanisms for resistance or sensitivity to pre-existing anti-measles immunity are not yet understood. Different hypotheses are discussed here, which will be important to investigate for further development of the measles-vectored vaccine platform.IMPORTANCESARS-CoV-2 emerged at the end of 2019 and rapidly spread worldwide causing the COVID-19 pandemic that urgently called for vaccines. We developed a vaccine candidate using the highly efficacious measles vaccine as vector, a technology which has proved highly promising in clinical trials for other pathogens. We report here and in the companion article by Nambulli et al. (J Virol 98:e01762-23, 2024, https://doi.org/10.1128/jvi.01762-23) the design, selection, and preclinical efficacy of the V591 vaccine candidate that was moved into clinical development in August 2020, 7 months after the identification of SARS-CoV-2 in Wuhan. These unique in-human trials of a measles vector-based COVID-19 vaccine revealed insufficient immunogenicity, which may be the consequence of previous exposure to the pediatric measles vaccine. The three studies together in mice, primates, and humans provide a unique insight into the measles-vectored vaccine platform, raising potential limitations of surrogate preclinical models and calling for further refinement of the platform.

Immunogenicity and efficacy of XBB.1.5 rS vaccine against the EG.5.1 variant of SARS-CoV-2 in Syrian hamsters.

The continued emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates updating coronavirus disease 2019 (COVID-19) vaccines to match circulating strains. The immunogenicity and efficacy of these vaccines must be tested in pre-clinical animal models. In Syrian hamsters, we measured the humoral and cellular immune response after immunization with the nanoparticle recombinant Spike (S) protein-based COVID-19 vaccine (Novavax, Inc.). We also compared the efficacy of the updated monovalent XBB.1.5 variant vaccine with previous COVID-19 vaccines for the induction of XBB.1.5 and EG.5.1 neutralizing antibodies and protection against a challenge with the EG.5.1 variant of SARS-CoV-2. Immunization induced high levels of S-specific IgG and IgA antibody-secreting cells and antigen-specific CD4+ T cells. The XBB.1.5 and XBB.1.16 vaccines, but not the Prototype vaccine, induced high levels of neutralizing antibodies against the XBB.1.5, EG.5.1, and JN.1 variants of SARS-CoV-2. Upon challenge with the Omicron EG.5.1 variant, the XBB.1.5 and XBB.1.16 vaccines reduced the virus load in the lungs, nasal turbinates, trachea, and nasal washes. The bivalent vaccine (Prototype rS + BA.5 rS) continued to offer protection in the trachea and lungs, but protection was reduced in the upper airways. By contrast, the monovalent Prototype vaccine no longer offered good protection, and breakthrough infections were observed in all animals and tissues. Thus, based on these study results, the protein-based XBB.1.5 vaccine is immunogenic and increased the breadth of protection against the Omicron EG.5.1 variant in the Syrian hamster model. IMPORTANCE: As SARS-CoV-2 continues to evolve, there is a need to assess the immunogenicity and efficacy of updated vaccines against newly emerging variants in pre-clinical models such as mice and hamsters. Here, we compared the immunogenicity and efficacy between the updated XBB.1.5, the original Prototype Wuhan-1, and the bivalent Prototype + BA.5 vaccine against a challenge with the EG.5.1 Omicron variant of SARS-CoV-2 in hamsters. The XBB.1.5 and bivalent vaccine, but not the Prototype, induced serum-neutralizing antibodies against EG.5.1, albeit the titers were higher in the XBB.1.5 immunized hamsters. The presence of neutralizing antibodies was associated with complete protection against EG.5.1 infection in the lower airways and reduced virus titers in the upper airways. Compared with the bivalent vaccine, immunization with XBB.1.5 improved viral control in the nasal turbinates. Together, our data show that the updated vaccine is immunogenic and that it offers better protection against recent variants of SARS-CoV-2.

Cardiovascular events following coronavirus disease 2019 vaccination in adults: a nationwide Swedish study.

BACKGROUND AND AIMS: While the rationale for coronavirus disease 2019 (COVID-19) vaccination is to reduce complications and overall mortality, some cardiovascular complications from the vaccine itself have been demonstrated. Myocarditis and pericarditis are recognized as rare acute adverse events after mRNA vaccines in young males, while evidence regarding other cardiovascular events remains limited and inconsistent. This study assessed the risks of several cardiovascular and cerebrovascular events in a Swedish nationwide register-based cohort. METHODS: Post-vaccination risk of myocarditis/pericarditis, dysrhythmias, heart failure, myocardial infarction, and cerebrovascular events (transient ischaemic attack and stroke) in several risk windows after each vaccine dose were assessed among all Swedish adults (n = 8 070 674). Hazard ratios (HRs) with 95% confidence intervals (95% CIs) compared with unvaccinated were estimated from Cox regression models adjusted for potential confounders. RESULTS: For most studied outcomes, decreased risks of cardiovascular events post-vaccination were observed, especially after dose three (HRs for dose three ranging from .69 to .81), while replicating the increased risk of myocarditis and pericarditis 1-2 weeks after COVID-19 mRNA vaccination. Slightly increased risks, similar across vaccines, were observed for extrasystoles [HR 1.17 (95% CI 1.06-1.28) for dose one and HR 1.22 (95% CI 1.10-1.36) for dose two, stronger in elderly and males] but not for arrhythmias and for transient ischaemic attack [HR 1.13 (95% CI 1.05-1.23), mainly in elderly] but not for stroke. CONCLUSIONS: Risk of myopericarditis (mRNA vaccines only), extrasystoles, and transient ischaemic attack was transiently increased after COVID-19 vaccination, but full vaccination substantially reduced the risk of several more severe COVID-19-associated cardiovascular outcomes, underscoring the protective benefits of complete vaccination.

Thromboembolism after coronavirus disease 2019 vaccination in atrial fibrillation/flutter: a self-controlled case series study.

BACKGROUND AND AIMS: Concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines in patients with atrial fibrillation/flutter (AF/AFL) have arisen due to reports of thrombo-embolic events following COVID-19 vaccination in the general population. This study aimed to evaluate the risk of thrombo-embolic events after COVID-19 vaccination in patients with AF/AFL. METHODS: This was a modified self-controlled case-series study using a comprehensive nationwide-linked database provided by the National Health Insurance Service in South Korea to calculate incidence rate ratios (IRRs) of thrombo-embolic events. The study population included individuals aged ≥12 years who were either vaccinated (e.g. one or two doses) or unvaccinated during the period from February to December 2021. The primary outcome was a composite of thrombo-embolic events, including ischaemic stroke, transient ischaemic attack, and systemic thromboembolism. The risk period was defined as 0-21 days following COVID-19 vaccination. RESULTS: The final analysis included 124 127 individuals with AF/AFL. The IRR of thrombo-embolic events within 21 days after COVID-19 vaccination, compared with that during the unexposed control period, was 0.93 [95% confidence interval (CI) 0.77-1.12]. No significant risk variations were noted by sex, age, or vaccine type. However, patients without anticoagulant therapy had an IRR of 1.88 (95% CI 1.39-2.54) following vaccination. CONCLUSIONS: In patients with AF/AFL, COVID-19 vaccination was generally not associated with an increased risk of thrombo-embolic events. However, careful individual risk assessment is required when advising vaccination for those not on oral anticoagulant, as these patients exhibited an increased risk of thrombo-embolic events post-vaccination.

An Observational Prospective Cohort Study of Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection of an Aerosolized, Inhaled Adenovirus Type 5-Vectored Coronavirus Disease 2019 Vaccine Given as a Second Booster Dose in Guangzhou City, China.

Using a prospective, observational cohort study during the post-"dynamic COVID-zero" wave in China, we estimated short-term relative effectiveness against Omicron BA.5 infection of inhaled aerosolized adenovirus type 5-vectored ancestral strain coronavirus disease 2019 (COVID-19) vaccine as a second booster dose approximately 1 year after homologous boosted primary series of inactivated COVID-19 vaccine compared with no second booster. Participants reported nucleic acid or antigen test results weekly until they tested positive or completed predesignated follow-up. After excluding participants infected <14 days after study entry, relative effectiveness among the 6576 participants was 61% in 18- to 59-year-olds and 38% in ≥60-year-olds and was sustained for 12 weeks.

Association Between SARS-CoV-2 Viral Load and COVID-19 Vaccination in 4 Phase 3 Trials.

Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity-IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

BACKGROUND: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. METHODS: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. RESULTS: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. CONCLUSIONS: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

COVID-19 vaccinated children, adolescents, and young adults with acute lymphoblastic leukemia show spike reactive antibodies and multifunctional T-cells.

Little is known about the efficacy of COVID-19 vaccines during acute lymphoblastic leukemia therapy (ALL); data for COVID-19 vaccine immune responses in pediatric leukemia remain sparse. We conducted a single center study of patients aged 5-25 years undergoing ALL chemotherapy who received COVID-19 vaccination. Twenty-one patients were enrolled; efficacy was evaluable in 20. Twenty were vaccinated while receiving chemotherapy. Twenty received the BNT162b2 mRNA vaccine. Spike reactive antibodies (S-IgG) and/or T-cells (SRT) were detected in 16 of 20 (80%) vaccinated patients; 13 (65%) and 9 (45%) were positive for S-IgG and SRT, respectively. Six (30%) showed both spike reactive B and T-cell responses. Eleven of the 13 with S-IgG positivity were negative for anti-Nucleocapsid IgG, an antibody profile consistent with a vaccine induced immune response. All 13S-IgG+ patients showed neutralizing antibodies. SRT included CD4+ (7) and CD8+ (6) T-cells; both CD4+ and CD8+ SRT were seen in 4. SRT were multifunctional (producing multiple cytokines) in most patients (8 of 9); 4 showed SRT with triple cytokine and B-cell co-stimulatory responses, indicating a multimodal adaptive immune response. Immune responses were seen among patients vaccinated in the settings of lymphopenia (6 of 12) intensive chemotherapy (3 of 4), and Peg allergy (6 of 8). Sequencing revealed public CD4+ and CD8+ TCR sequences reactive to epitopes across the spike protein. In conclusion, COVID-19 vaccination induced B and/or T-cell responses in a majority of children and young adults undergoing ALL chemotherapy.

Applying two approaches to detect unmeasured confounding due to time-varying variables in a self-controlled risk interval design evaluating COVID-19 vaccine safety signals, using myocarditis as a case example.

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between 1 September 2020 and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and otitis externa (NCO). The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (i) baseline probability of the confounder was higher in the control window and (ii) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09, 95%CI 1.01-1.09). The QBA suggested even the strongest literature-reported confounder (COVID-19; RRmyocarditis = 18.3) could only explain away part of the observed effect from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion.

Strategic deactivation of mRNA COVID-19 vaccines: New applications for siRNA therapy and RIBOTACs.

The rapid development and authorization of messenger ribonucleic acid (mRNA) vaccines by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) in 2020 marked a significant milestone in human mRNA product application, overcoming previous obstacles such as mRNA instability and immunogenicity. This paper reviews the strategic modifications incorporated into these vaccines to enhance mRNA stability and translation efficiency, such as the inclusion of nucleoside modifications and optimized mRNA design elements including the 5' cap and poly(A) tail. We highlight emerging concerns regarding the wide systemic biodistribution of these mRNA vaccines leading to prolonged inflammatory responses and other safety concerns. The regulatory framework guiding the biodistribution studies is pivotal in assessing the safety profiles of new mRNA formulations in use today. The stability of mRNA vaccines, their pervasive distribution, and the longevity of the encapsulated mRNA along with unlimited production of the damaging and potentially lethal spike (S) protein call for strategies to mitigate potential adverse effects. Here, we explore the potential of small interfering RNA (siRNA) and ribonuclease targeting chimeras (RIBOTACs) as promising solutions to target, inactivate, and degrade residual and persistent vaccine mRNA, thereby potentially preventing uncontrolled S protein production and reducing toxicity. The targeted nature of siRNA and RIBOTACs allows for precise intervention, offering a path to prevent and mitigate adverse events of mRNA-based therapies. This review calls for further research into siRNA and RIBOTAC applications as antidotes and detoxication products for mRNA vaccine technology.

A controlled effects approach to assessing immune correlates of protection.

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect. To address this limitation, we construct the controlled risk curve of a biomarker, which provides the causal risk of an endpoint if all participants are assigned vaccine and the biomarker is set to different levels. Furthermore, we propose a causal CoP analysis based on controlled effects, where for the important special case that the biomarker is constant in the placebo arm, we study the controlled vaccine efficacy curve that contrasts the controlled risk curve with placebo arm risk. We provide identification conditions and formulae that account for right censoring of the clinical endpoint and two-phase sampling of the biomarker, and consider G-computation estimation and inference under a semiparametric model such as the Cox model. We add modular approaches to sensitivity analysis that quantify robustness of CoP evidence to unmeasured confounding. We provide an application to two phase 3 trials of a dengue vaccine indicating that controlled risk of dengue strongly varies with 50$\%$ neutralizing antibody titer. Our work introduces controlled effects causal mediation analysis to immune CoP evaluation.

Risk of encephalitis and meningitis after COVID-19 vaccination in South Korea: a self-controlled case series analysis.

BACKGROUND: Several neurological manifestations shortly after a receipt of coronavirus infectious disease 2019 (COVID-19) vaccine have been described in the recent case reports. Among those, we sought to evaluate the risk of encephalitis and meningitis after COVID-19 vaccination in the entire South Korean population. METHODS: We conducted self-controlled case series (SCCS) analysis using the COVID-19 immunization record data from the Korea Disease Control Agency between February 2021 and March 2022, linked with the National Health Insurance Database between January 2021 and October 2022. We retrieved all medical claims of adults aged 18 years or older who received at least one dose of COVID-19 vaccines (BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S), and included only those who had a diagnosis record for encephalitis or meningitis within the 240-day post-vaccination period. With day 0 defined as the date of vaccination, risk window was defined as days 1-28 and the control window as the remainder period excluding the risk windows within the 240-day period. We used conditional Poisson regression to estimate the incidence rate ratios (IRR) with 95% confidence intervals (CI), stratified by dose and vaccine type. RESULTS: From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 251 and 398 cases of encephalitis and meningitis during the risk window, corresponding to 1.9 and 3.1 cases per 1 million doses, respectively. Overall, there was an increased risk of encephalitis in the first 28 days of COVID-19 vaccination (IRR 1.26; 95% CI 1.08-1.47), which was only significant after a receipt of ChAdOx1-S (1.49; 1.03-2.15). For meningitis, no increased risk was observed after any dose of COVID-19 vaccine (IRR 1.03; 95% CI 0.91-1.16). CONCLUSIONS: Our findings suggest an overall increased risk of encephalitis after COVID-19 vaccination. However, the absolute risk was small and should not impede COVID-19 vaccine confidence. No significant association was found between the risk of meningitis and COVID-19 vaccination.

How effective is the BNT162b2 mRNA vaccine against SARS-CoV-2 transmission and infection? A national programme analysis in Monaco, July 2021 to September 2022.

BACKGROUND: We quantified SARS-CoV-2 dynamics in different community settings and the direct and indirect effect of the BNT162b2 mRNA vaccine in Monaco for different variants of concern (VOC). METHODS: Between July 2021 and September 2022, we prospectively investigated 20,443 contacts from 6320 index cases using data from the Monaco COVID-19 Public Health Programme. We calculated secondary attack rates (SARs) in households (n = 13,877), schools (n = 2508) and occupational (n = 6499) settings. We used binomial regression with a complementary log-log link function to measure adjusted hazard ratios (aHR) and vaccine effectiveness (aVE) for index cases to infect contacts and contacts to be infected in households. RESULTS: In households, the SAR was 55% (95% CI 54-57) and 50% (48-51) among unvaccinated and vaccinated contacts, respectively. The SAR was 32% (28-36) and 12% (10-13) in workplaces, and 7% (6-9) and 6% (3-10) in schools, among unvaccinated and vaccinated contacts respectively. In household, the aHR was lower in contacts than in index cases (aHR 0.68 [0.55-0.83] and 0.93 [0.74-1.1] for delta; aHR 0.73 [0.66-0.81] and 0.89 [0.80-0.99] for omicron BA.1&2, respectively). Vaccination had no significant effect on either direct or indirect aVE for omicron BA.4&5. The direct aVE in contacts was 32% (17, 45) and 27% (19, 34), and for index cases the indirect aVE was 7% (- 17, 26) and 11% (1, 20) for delta and omicron BA.1&2, respectively. The greatest aVE was in contacts with a previous SARS-CoV-2 infection and a single vaccine dose during the omicron BA.1&2 period (45% [27, 59]), while the lowest were found in contacts with either three vaccine doses (aVE - 24% [- 63, 6]) or one single dose and a previous SARS-CoV-2 infection (aVE - 36% [- 198, 38]) during the omicron BA.4&5 period. CONCLUSIONS: Protection conferred by the BNT162b2 mRNA vaccine against transmission and infection was low for delta and omicron BA.1&2, regardless of the number of vaccine doses and previous SARS-CoV-2 infection. There was no significant vaccine effect for omicron BA.4&5. Health authorities carrying out vaccination campaigns should bear in mind that the current generation of COVID-19 vaccines may not represent an effective tool in protecting individuals from either transmitting or acquiring SARS-CoV-2 infection.

Immune signature in vaccinated versus non-vaccinated aged people with COVID-19 pneumonia.

BACKGROUND: A definition of the immunological features of COVID-19 pneumonia is needed to support clinical management of aged patients. In this study, we characterized the humoral and cellular immune responses in presence or absence of SARS-CoV-2 vaccination, in aged patients admitted to the IRCCS San Raffaele Hospital (Italy) for COVID-19 pneumonia between November 2021 and March 2022. METHODS: The study was approved by local authorities. Disease severity was evaluated according to WHO guidelines. We tested: (A) anti-SARS-CoV-2 humoral response (anti-RBD-S IgG, anti-S IgM, anti-N IgG, neutralizing activity against Delta, BA1, BA4/5 variants); (B) Lymphocyte B, CD4 and CD8 T-cell phenotype; (C) plasma cytokines. The impact of vaccine administration and different variants on the immunological responses was evaluated using standard linear regression models and Tobit models for censored outcomes adjusted for age, vaccine doses and gender. RESULT: We studied 47 aged patients (median age 78.41), 22 (47%) female, 33 (70%) older than 70 years (elderly). At hospital admission, 36% were unvaccinated (VACno), whilst 63% had received 2 (VAC2) or 3 doses (VAC3) of vaccine. During hospitalization, WHO score > 5 was higher in unvaccinated (14% in VAC3 vs. 43% in VAC2 and 44% VACno). Independently from vaccination doses and gender, elderly had overall reduced anti-SARS-CoV-2 humoral response (IgG-RBD-S, p = 0.0075). By linear regression, the anti-RBD-S (p = 0.0060), B (p = 0.0079), CD8 (p = 0.0043) and Th2 cell counts (p = 0.0131) were higher in VAC2 + 3 compared to VACno. Delta variant was the most representative in VAC2 (n = 13/18, 72%), detected in 41% of VACno, whereas undetected in VAC3, and anti-RBD-S production was higher in VAC2 vs. VACno (p = 0.0001), alongside neutralization against Delta (p = 0141), BA1 (p = 0.0255), BA4/5 (p = 0.0162). Infections with Delta also drove an increase of pro-inflammatory cytokines (IFN-α, p = 0.0463; IL-6, p = 0.0010). CONCLUSIONS: Administration of 3 vaccination doses reduces the severe symptomatology in aged and elderly. Vaccination showed a strong association with anti-SARS-CoV-2 humoral response and an expansion of Th2 T-cells populations, independently of age. Delta variants and number of vaccine doses affected the magnitude of the humoral response against the original SARS-CoV-2 and emerging variants. A systematic surveillance of the emerging variants is paramount to define future vaccination strategies.