A speed limit on serial strain replacement from original antigenic sin.

Many pathogens evolve to escape immunity, yet it remains difficult to predict whether immune pressure will lead to diversification, serial replacement of one variant by another, or more complex patterns. Pathogen strain dynamics are mediated by cross-protective immunity, whereby exposure to one strain partially protects against infection by antigenically diverged strains. There is growing evidence that this protection is influenced by early exposures, a phenomenon referred to as original antigenic sin (OAS) or imprinting. In this paper, we derive constraints on the emergence of the pattern of successive strain replacements demonstrated by influenza, SARS-CoV-2, seasonal coronaviruses, and other pathogens. We find that OAS implies that the limited diversity found with successive strain replacement can only be maintained if [Formula: see text] is less than a threshold set by the characteristic antigenic distances for cross-protection and for the creation of new immune memory. This bound implies a "speed limit" on the evolution of new strains and a minimum variance of the distribution of infecting strains in antigenic space at any time. To carry out this analysis, we develop a theoretical model of pathogen evolution in antigenic space that implements OAS by decoupling the antigenic distances required for protection from infection and strain-specific memory creation. Our results demonstrate that OAS can play an integral role in the emergence of strain structure from host immune dynamics, preventing highly transmissible pathogens from maintaining serial strain replacement without diversification.

Phase 1, randomized, rater and participant blinded placebo-controlled study of the safety, reactogenicity, tolerability and immunogenicity of H1N1 influenza vaccine delivered by VX-103 (a MIMIX microneedle patch [MAP] system) in healthy adults.

BACKGROUND: The MIMIX platform is a novel microneedle array patch (MAP) characterized by slowly dissolving microneedle tips that deploy into the dermis following patch application. We describe safety, reactogenicity, tolerability and immunogenicity for MIMIX MAP vaccination against influenza. METHODOLOGY: The trial was a Phase 1, exploratory, first-in-human, parallel randomized, rater, participant, study analyst-blinded, placebo-controlled study in Canada. Forty-five healthy participants (18 to 39 years of age, inclusive) were randomized in a 1:1:1 ratio to receive either 15 µg or 7.5 µg of an H1N1 influenza vaccine, or placebo delivered via MIMIX MAP to the volar forearm. A statistician used a computer program to create a randomization scheme with a block size of 3. Post-treatment follow-up was approximately 180 days. Primary safety outcomes included the incidence of study product related serious adverse events and unsolicited events within 180 days, solicited application site and systemic reactogenicity through 7 days after administration and solicited application site erythema and/or pigmentation 14, 28, 56 and 180 days after administration. Immunogenicity outcomes included antibody titers and percentage of seroconversion (SCR) and seroprotection (SPR) rates determined by the hemagglutination inhibition (HAI) assay. Exploratory outcomes included virus microneutralization (MN) titers, durability and breadth of the immune response. The trial was registered with ClinicalTrials.gov, number NCT06125717. FINDINGS: Between July 7, 2022 and March 13, 2023 45 participants were randomized to a treatment group. One participant was lost to follow up in the 15 µg group and 1 participant withdrew from the 7.5 µg dose group. Safety analyses included n = 15 per group, immunogenicity analyses included n = 14 for the 15 µg and 7.5 µg treatment groups and n = 15 for the placebo group. No SAEs were reported in any of the treatment groups. All treatment groups reported solicited local events within 7 days after vaccination, with mild (Grade 1) erythema being the most frequent symptom reported. Other local symptoms reported included mostly mild (Grade 1) induration/swelling, itching, pigmentation, skin flaking, and tenderness. Within 7 days after vaccination, 2 participants (4.4%) reported moderate (Grade 2) erythema, 1 participant (2.2%) reported moderate (Grade 2) induration/swelling, and 1 participant (2.2%) reported moderate (Grade 2) itching. There was an overall reduction in erythema and pigmentation reported on Days 15, 29, 57, and 180 among all treatment groups. Systemic symptoms reported within 7 days after vaccination, included mild (Grade 1) fatigue reported among all treatment groups, and mild (Grade 1) headache reported by 1 participant in the 7.5 µg treatment group. No study drug related severe symptoms were reported in the study. Group mean fold rises in HAI titers ranged between 8.7 and 12-fold, SCRs were >76% and SPRs were >92% for both VX-103 dose groups thereby fulfilling serological criteria established by the EMA and FDA for seasonal influenza vaccines. Longitudinal assessments demonstrate persistence of the immune response through at least Day 180. CONCLUSIONS: The MIMIX MAP platform is safe, well tolerated and elicits robust antibody responses.

Medical and dental student knowledge about COVID-19 and influenza vaccines impact opinions about vaccine advocacy and future practice.

Introduction: The World Health Organization has identified vaccine hesitancy as a global public health challenge. Healthcare providers are among the most influential and trusted figures for vaccine counseling. This article focuses on COVID-19 and influenza personal immunization behaviors, vaccine knowledge and opinions, and vaccine counseling confidence among future healthcare providers - dental and medical students. Methods: A cross-sectional anonymous online survey was conducted at four dental schools and one allopathic medical school in the United States. Items included personal vaccination status for the COVID-19 and influenza vaccines and vaccine-specific items developed based on past research to assess knowledge, opinions, and behaviors. Results: Two hundred and thirty-two medical and 221 dental students completed the survey. 68 and 55% scored average/above-average knowledge on COVID-19 and influenza vaccine items, respectively. There were significant differences between those with average/above-average and below-average knowledge scores regarding learning about, recommending, and advocating for vaccines and counseling vaccine-hesitant patients for both vaccines (p < 0.0001). Although higher-knowledge students had higher vaccination rates (p < 0.0001), many had insufficient knowledge about vaccines. Discussion: Healthcare providers play a crucial role in vaccine advocacy. The identified knowledge gaps are significant as they impact quality of patient care. And opinions about future vaccination practice such as recommending, providing, and counseling about vaccines. Equipping students with knowledge and communication skills will enable them to be strong vaccine advocates to improve overall public health.

SARS-CoV-2 and influenza vaccine hesitancy during the COVID-19 pandemic in a dynamic perspective.

To investigate the dynamic evolution of vaccine hesitancy toward both COVID-19 and influenza in a context characterized by the compresence of SARS-CoV-2 pandemic and seasonal flu epidemics, a two times repeated cross-sectional exploratory design was performed at Udine Hospital (Italy) following a cohort of 479 adult patients with a previous history of SARS-CoV-2 infection in 2020. Vaccine attitude was assessed through standardized telephone interviews performed at 12 and 18 months after the acute illness. The first interview reported the success of the 2020/21 seasonal influenza immunization with 46.8% (224/479) of the participants showing a positive attitude, especially the elderly and people with comorbidities (p < .001), but the investigation conducted at 18 months showed a drastic drop in flu shot acceptance (30/166, 18.1%). On the other hand, a great increase in vaccinations against SARS-CoV-2 occurred after the introduction of Green Pass (26.7% vs 72.9%). The major drivers of flu vaccine skepticism were represented by the feeling of protection regardless of prevention and by concerns regarding vaccines safety and efficacy; conversely compulsory strategies seemed to play a secondary role, since only a minority of the participants identified in the restrictions induced by the certification the major incentive to get immunized against SARS-CoV-2. The focus on this peculiar historical period helps to take a step forward in the comprehension of the complexity and dynamicity of the vaccine hesitancy phenomenon. Future vaccination campaigns will need to consider the role of personal opinions and emotions, interpreted according to the social and political context.

Predicting seasonal influenza outbreaks with regime shift-informed dynamics for improved public health preparedness.

In this study, we propose a novel approach that integrates regime-shift detection with a mechanistic model to forecast the peak times of seasonal influenza. The key benefit of this approach is its ability to detect regime shifts from non-epidemic to epidemic states, which is particularly beneficial with the year-round presence of non-zero Influenza-Like Illness (ILI) data. This integration allows for the incorporation of external factors that trigger the onset of the influenza season-factors that mechanistic models alone might not adequately capture. Applied to ILI data collected in Korea from 2005 to 2020, our method demonstrated stable peak time predictions for seasonal influenza outbreaks, particularly in years characterized by unusual onset times or epidemic magnitudes.

Epidemic patterns of the different influenza virus types and subtypes/lineages for 10 years in Chongqing, China, 2010-2019.

To optimize seasonal influenza control and prevention programs in regions with potentially complicated seasonal patterns. Descriptive epidemiology was used to analyze the etiology of influenza, and chi-square tests were used to compare the epidemic patterns among different influenza virus types and subtypes/lineages. From January 2010 to December 2019, a total of 63,626 ILI cases were reported in Chongqing and 14,136 (22.22%) were laboratory-confirmed influenza cases. The proportions of specimens positive for influenza A and influenza B were 13.32% (8,478/63,626) and 8.86% (5,639/63,626), respectively. The proportion of positive specimens for influenza A reached the highest in winter (23.33%), while the proportion of positive specimens for influenza B reached the highest in spring (11.88%). Children aged 5-14 years old had the highest proportion of positive specimens for influenza. The influenza virus types/subtypes positive was significantly different by seasons and age groups (P<.001), but not by gender (p = .436). The vaccine strains were matched to the circulating influenza virus strains in all other years except for 2018 (vaccine strain was B/Colorado/06/2017; circulating strain was B/Yamagata). The study showed significant variations in epidemic patterns, including seasonal epidemic period and age distributions, among different influenza types, subtypes/lineages in Chongqing. Influenza vaccines matched to the circulating influenza virus strain in nine of the ten years. To prevent and mitigate the influenza outbreaks in this area, high risk population, especially children aged 5-14 years, are encouraged to get vaccinated against influenza before the epidemic seasons.

Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface.

Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized the IBV neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Competition-binding experiments suggested the antibodies recognized two major antigenic sites. One group, which included mAb FluB-393, broadly inhibited IBV NA sialidase activity, protected prophylactically in vivo, and bound to the lateral corner of NA. The second group contained an active site mAb, FluB-400, that broadly inhibited IBV NA sialidase activity and virus replication in vitro in primary human respiratory epithelial cell cultures and protected against IBV in vivo when administered systemically or intranasally. Overall, the findings described here shape our mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates.

Influenza Vaccination Requirements for Health Care Personnel in US Hospitals.

This survey study assesses changes from 2017 to 2021 in self-reported annual influenza vaccination among workers in nonfederal and Veterans Affairs hospitals.

Association between influenza vaccination and one-year all-cause and cardiovascular mortality risk: A self-controlled case series and matched case-control study.

Debates surrounding the efficacy of influenza vaccination for survival benefits persist, and there is a lack of data regarding its duration of protection. A self-controlled case series (SCCS) and a 1:4 matched case-control study were conducted using the National Health Interview Survey (NHIS) and public-use mortality data from 2005 to 2018 in the United States. The SCCS study identified participants who received influenza vaccination within 12 months before the survey and subsequently died within 1 year of postvaccination. The matched case-control study paired participants who died during the influenza season at the time of survey with four survivors. Among 1167 participants in the SCCS study, there was a 46% reduction in all-cause mortality and a 43% reduction in cardiovascular mortality within 29-196 days of postvaccination. The greatest protection was observed during days 29-56 (all-cause mortality: RI: 0.19; 95% CI: 0.12-0.29; cardiovascular mortality: RI: 0.28; 95% CI: 0.14-0.56). Among 626 cases and 2504 controls included in the matched case-control study, influenza vaccination was associated with a reduction in all-cause mortality (OR: 0.74, 95% CI: 0.60-0.92) and cardiovascular mortality (OR: 0.64, 95% CI: 0.44-0.93) during the influenza season. This study highlights the importance of influenza vaccination in reducing the risks of all-cause and cardiovascular mortality, with effects lasting for approximately 6 months.

Inactivated influenza virus vaccines expressing COBRA hemagglutinin elicited broadly reactive, long-lived protective antibodies.

The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.

The economic rationale for cell-based influenza vaccines in children and adults: A review of cost-effectiveness analyses.

Seasonal influenza significantly affects both health and economic costs in children and adults. This narrative review summarizes published cost-effectiveness analyses (CEAs) of cell-based influenza vaccines in children and adults <65 years of age, critically assesses the assumptions and approaches used in these analyses, and considers the role of cell-based influenza vaccines for children and adults. CEAs from multiple countries demonstrated the cost-effectiveness of cell-based quadrivalent influenza vaccines (QIVc) compared with egg-based trivalent/quadrivalent influenza vaccines (TIVe/QIVe). CEA findings were consistent across models relying on different relative vaccine effectiveness (rVE) estimate inputs, with the rVE of QIVc versus QIVe ranging from 8.1% to 36.2% in favor of QIVc. Across multiple scenarios and types of analyses, QIVc was consistently cost-effective compared with QIVe, including in children and adults across different regions of the world.

Predictors of parental acceptance to live attenuated influenza vaccine for children.

To determine the influencing factors of Chinese parents' intention and behavior for children to receive live attenuated influenza vaccine during the 2022-2023 influenza season. A theoretical model was developed and included seven constructs, and structural equation modeling was used to test 11 hypotheses. From October 2022 to December 2023, a survey was conducted across 38 medical institutions in four Chinese cities and their subordinate districts, counties, and rural areas. Parents who accompanied their children for vaccinations were selected through a randomization process based on their child's medical card numbers. Measures were taken to minimize method bias, including a diverse geographical representation and random sampling. The survey resulted in the collection of 936 valid responses, exceeding the recommended sample size for structural equation model analysis and providing robust statistical inferences. During the study period, 936 respondents were included in the study. Perceived ease of use was verified to be a predictor of perceived usefulness and perceived value. Perceived usefulness was verified as a predictor of perceived value and behavioral intention. Knowledge was a significant antecedent of perceived value and risk perception of influenza disease. Risk perception of influenza disease was proved to be a significant predictor of perceived value and self-reported vaccination behavior. Perceived value significantly affected behavioral intention, and behavioral intention significantly affected self-reported vaccination behavior. Six demographic variables significantly moderate the theoretical models. The low vaccination coverage of live attenuated influenza vaccine (LAIV) among children in China suggests a need for a deeper understanding of the factors that influence vaccination rates. Particularly, effective strategies are necessary from policymakers and practitioners to elevate childhood LAIV coverage.

Immunity by AS03ation: The natural adjuvantage.

Humans do not respond equally to vaccination. To investigate why, Mulè et al. developed a multimodal framework and found that high responders after unadjuvanted influenza vaccination exist in a naturally adjuvanted state, mimicking innate immunophenotypes following AS03-adjuvanted vaccination. This highlights biological factors that set apart high-antibody responders and how adjuvants can boost innate immune cues to improve humoral immunity.

Exploring barriers to influenza vaccine uptake and recommendation among healthcare providers in the community in China: A qualitative study.

Healthcare providers (HCPs) are recommended for priority influenza vaccination due to their high risk of contracting influenza. HCPs greatly aid in targeted population immunization campaigns. Therefore, understanding the factors that influence HCPs' decisions to get vaccinated and to recommend influenza vaccination is essential. However, there currently needs to be more evidence on this topic in China. Qualitative interviews using a semi-structured interview method were conducted with 180 HCPs from urban community hospitals and town hospitals in four cities in Shandong Province during August 2023. The interview content was analyzed using thematic analysis to identify the variables impacting the vaccination and recommendation practices of HCPs, as well as their suggestions for improving vaccination services. The results will help support the future development of precise intervention measures as well as focused education and training.

Natural Product-Derived Phytochemicals for Influenza A Virus (H1N1) Prevention and Treatment.

Influenza A (H1N1) viruses are prone to antigenic mutations and are more variable than other influenza viruses. Therefore, they have caused continuous harm to human public health since the pandemic in 2009 and in recent times. Influenza A (H1N1) can be prevented and treated in various ways, such as direct inhibition of the virus and regulation of human immunity. Among antiviral drugs, the use of natural products in treating influenza has a long history, and natural medicine has been widely considered the focus of development programs for new, safe anti-influenza drugs. In this paper, we focus on influenza A (H1N1) and summarize the natural product-derived phytochemicals for influenza A virus (H1N1) prevention and treatment, including marine natural products, flavonoids, alkaloids, terpenoids and their derivatives, phenols and their derivatives, polysaccharides, and derivatives of natural products for prevention and treatment of influenza A (H1N1) virus. We further discuss the toxicity and antiviral mechanism against influenza A (H1N1) as well as the druggability of natural products. We hope that this review will facilitate the study of the role of natural products against influenza A (H1N1) activity and provide a promising alternative for further anti-influenza A drug development.

Promotion of Influenza Vaccination in the Emergency Department.

BACKGROUND: Influenza vaccine uptake is low among underserved populations whose primary health care access occurs in emergency departments. We sought to determine whether implementation of two interventions would increase 30-day influenza vaccine uptake in unvaccinated patients in the emergency department. METHODS: This three-group, prospective, cluster-randomized controlled trial compared two interventions with a control group in noncritically ill, adult patients in the emergency department who were not vaccinated for influenza in the current vaccine season. The unit of randomization was individual calendar days. Participants received either Intervention M (an influenza vaccine messaging platform consisting of a video, one-page flyer, and scripted message, followed by a vaccine acceptance question and provider notification if participants indicated vaccine acceptance), Intervention Q (no messaging but the vaccine acceptance question and provider notification), or control (usual care/no intervention). The primary outcome was receipt of an influenza vaccine at 30 days ascertained by electronic health record review and telephone follow-up, comparing the Intervention M group with the control group. Secondary outcomes included comparisons of 30-day vaccine uptake in Intervention Q versus control and Intervention M versus Intervention Q. RESULTS: Between October 2022 and February 2023, a total of 767 trial participants were enrolled at six emergency departments in five U.S. cities. Median age was 46 years; 353 (46%) participants were female, 274 (36%) were African American, and 158 (21%) were Latinx; 126 (16%) lacked health insurance, and 244 (32%) lacked primary care. The Intervention M, Intervention Q, and control groups had 30-day vaccine uptakes of 41%, 32%, and 15%, respectively (P<0.0001 for Intervention M vs. control). Comparing Intervention M versus Intervention Q, the adjusted difference in 30-day vaccine uptake was 8.7 percentage points (95% confidence interval, -0.1 to 17.6 percentage points). CONCLUSIONS: Implementation of influenza vaccine messaging platforms (video clips, printed materials, and verbal scripts) improved 30-day vaccine uptake among unvaccinated patients in the emergency department. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05836818.).