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This study was to evaluate the sufficient safety and effect of the novel influenza vaccine program. It prepared new reassortant influenza virus, with high yield on Vero cells. According to the plaque counting, one dose LAIV was composed with 105 PFU of H1, H3, BY, and BV, respectively. Then mixed this LAIV with compound adjuvant, containing 500 μg/mL of carbopol971P and 50 μg/mL of tetanus toxin. That vaccination was called catt‐flu. And it employed the GYZZ02 vaccine (commercialized freeze‐dried LAIV, listed in China) as cohort analysis control. All mice received two doses of the vaccine, administered on days 0 and 14, respectively. That catt‐flu program could induce more cross‐protection with neutralizing antibody against heterogeneous types of influenza virus, not only based on HA but also NA protective antigen, through convenient nasal immunization, which had non‐inferiority titter compared with the chicken embryo‐derived GYZZ02 vaccine on safe and effect. The Vero cell‐derived vaccine (LAIV) combined compound catt adjuvant (contain carbopol971P and tetanus toxin) could provide another safety and protective program of influenza vaccine by intranasal administration, as catt‐flu program. [ABSTRACT FROM AUTHOR]

Antigen-specific T cells are an important part of antiviral responses, and modern influenza vaccines are designed to induce this mode of immunity. Live attenuated influenza vaccine (LAIV) is a potent inducer of T-cell immunity because of its ability to cause productive infection in the upper respiratory tract. Inactivated influenza vaccines (IIV) and novel vaccine candidates can also induce virus-specific T-cells when appropriate adjuvants are used. In this case, non-structural and intrinsic antigens of the master donor viruses, particularly nucleoprotein (NP), are the main targets for the development of T-cell immunity. The most commonly used donor strains for LAIVs and IIVs worldwide were derived from viruses isolated between 1933 and 1960. In this regard, the question of conservation of epitopes immunogenic for CD8⁺ T-lymphocytes (CTL-epitopes) in donor-derived NPs, i.e., the ability of cytotoxic T cells specific to the donor’s NP to recognize modern influenza A virus nucleoproteins, is relevant. The aim of the study was to evaluate the conservation of CTL-immunogenic NP epitopes of donors traditionally used to create LAIVs and IIVs. Materials and methods. Epitope NP analysis was performed for 1614 and 1767 strains of influenza A virus subtypes H1N1 and H3N2, respectively, which circulated in 2009–2023 (data from the NCBI Influenza Virus Database). Immune Epitope Database (IEDB, www.iedb.org), NetCTL’s built-in CTL-epitope prediction algorithm and NetChop proteolysis site predictor were used. CTL-epitopes were mapped to NPs of master donor viruses A/Leningrad/134/17/57 (H2N2), A/Ann Arbor/6/60 (H2N2), A/PR/8/34 (H1N1), and A/WSN/1933 (H1N1) using the CrustalO alignment algorithm in JalView 2.8.1 Software. The immunogenicity and conservation of selected epitopes were further evaluated using IEDB T-cell Immunogenicity Predictor and Epitope Conservancy Assay, respectively. Results. The majority of immunogenic CTL-epitopes of donor viruses proved to be non-conserved, i.e., not found in NPs of circulating influenza strains. Conversely, most CTL-immunogenic NP epitopes of modern viruses are absent in donor viruses and cannot be induced by vaccination with conventional vaccines. The data obtained indicate the need to actualize NP in vaccine composition by directed mutagenesis of the donor-derived NP gene or by introduction of the gene encoding NP of circulating influenza viruses into vaccine strains.

Live attenuated influenza vaccines (LAIV) typically induce a poor hemagglutination inhibition (HI) response, which is the standard correlate of protection for inactivated influenza vaccines. The significance of the HI response is complicated because the LAIV vaccine primarily induces the local mucosal immune system, while the HI assay measures the circulating serum antibody response. However, age and pre-existing immunity have been identified as important factors affecting LAIV immunogenicity. This study aimed to extend our understanding of LAIV-induced immunity, particularly, the impact age and pre-existing immunity have on eliciting functional and neutralising antibody responses in paediatric and adult populations vaccinated with LAIV. Thirty-one children and 26 adults were immunized with the trivalent LAIV during the 2013–2014 influenza season in Norway. Children under 9 years received a second dose of LAIV 28 days after the first dose. Blood samples were collected pre- and post-vaccination. HI, microneutralization (MN) and enzyme-linked lectin assay for neuraminidase (NA) antibodies were measured against the vaccine strains. IgG antibody avidity against hemagglutinin (HA) and NA proteins from the vaccine strains was also assessed. Significant correlations were observed between HI and MN responses to A/California/7/2009 (A/H1N1)pdm09-like strain and B/Massachusetts/2/2012-like strain, suggesting that MN is a potential immunological correlate for LAIV. However, the relationship between recipient age (or priming status) and serological response varied between vaccine strains. There was a notable increase in HI and MN responses in all cohorts except naive children against the H1N1 strain, where most recipients had responses below the protective antibody threshold. NAI responses were generally weak in naive children against all vaccine strains compared with adults or antigen-primed children. Post-vaccination antibody avidity increased only in primed children below nine years of age against the A/H1N1 strain. Overall, our findings indicate that LAIV elicits functional and neutralizing antibody responses in both naive and antigen experienced cohorts, however, the magnitude and kinetics of the response varies between vaccine strains. [ABSTRACT FROM AUTHOR]

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.

Between 2013 and 2016, the A/H1N1pdm09 component of the live attenuated influenza vaccine (LAIV) produced instances of lower-than-expected vaccine effectiveness. Standard pre-clinical ferret models, using a human-like vaccine dose and focusing on antigenic match to circulating wildtype (wt) strains, were unable to predict these fluctuations. By optimising the vaccine dose and utilising clinically relevant endpoints, we aimed to develop a ferret efficacy model able to reproduce clinical observations. Ferrets were intranasally vaccinated with 4 Log10 FFU/animal (1000-fold reduction compared to clinical dose) of seven historical LAIV formulations with known (19–90%) H1N1 vaccine efficacy or effectiveness (VE). Following homologous H1N1 wt virus challenge, protection was assessed based on primary endpoints of wt virus shedding in the upper respiratory tract and the development of fever. LAIV formulations with high (82–90%) H1N1 VE provided significant protection from wt challenge, while formulations with reduced (19–32%) VE tended not to provide significant protection. The strongest correlation observed was between reduction in wt shedding and VE (R2 = 0.75). Conversely, serum immunogenicity following vaccination was not a reliable indicator of protection (R2 = 0.37). This demonstrated that, by optimisation of the vaccine dose and the use of non-serological, clinically relevant protection endpoints, the ferret model could successfully translate clinical H1N1 LAIV VE data.

Background: Influenza viruses continue to cause a significant social and economic burden globally. Vaccination is recognized as the most effective measure to control influenza. Live attenuated influenza vaccines (LAIVs) are an effective means of preventing influenza, especially among children. A reverse genetics (RG) system is required to rapidly update the antigenic composition of vaccines, as well as to design LAIVs with a broader spectrum of protection. Such a system has been developed for the Russian LAIVs only for type A strains, but not for influenza B viruses (IBV). Methods: All genes of the B/USSR/60/69 master donor virus (B60) were cloned into RG plasmids, and the engineered B60, as well as a panel of IBV LAIV reassortants were rescued from plasmid DNAs encoding all viral genes. The engineered viruses were evaluated in vitro and in a mouse model. Results: The B60 RG system was successfully developed, which made it possible to rescue LAIV reassortants with the desired antigenic composition, including hybrid strains with hemagglutinin and neuraminidase genes belonging to the viruses from different IBV lineages. The LAIV candidate carrying the HA of the B/Victoria-lineage virus and NA from the B/Yamagata-lineage virus demonstrated optimal characteristics in terms of safety, immunogenicity and cross-protection, prompting its further assessment as a broadly protective component of trivalent LAIV. Conclusions: The new RG system for B60 MDV allowed the rapid generation of type B LAIV reassortants with desired genome compositions. The generation of hybrid LAIV reassortants with HA and NA genes belonging to the opposite IBV lineages is a promising approach for the development of IBV vaccines with broad cross-protection. [ABSTRACT FROM AUTHOR]

Live attenuated influenza vaccines (LAIV) typically induce a poor hemagglutination inhibition (HI) response, which is the standard correlate of protection for inactivated influenza vaccines. The significance of the HI response is complicated because the LAIV vaccine primarily induces the local mucosal immune system, while the HI assay measures the circulating serum antibody response. However, age and pre-existing immunity have been identified as important factors affecting LAIV immunogenicity. This study aimed to extend our understanding of LAIV-induced immunity, particularly, the impact age and pre-existing immunity have on eliciting functional and neutralising antibody responses in paediatric and adult populations vaccinated with LAIV. Thirty-one children and 26 adults were immunized with the trivalent LAIV during the 2013–2014 influenza season in Norway. Children under 9 years received a second dose of LAIV 28 days after the first dose. Blood samples were collected pre- and post-vaccination. HI, microneutralization (MN) and enzyme-linked lectin assay for neuraminidase (NA) antibodies were measured against the vaccine strains. IgG antibody avidity against hemagglutinin (HA) and NA proteins from the vaccine strains was also assessed. Significant correlations were observed between HI and MN responses to A/California/7/2009 (A/H1N1)pdm09-like strain and B/Massachusetts/2/2012-like strain, suggesting that MN is a potential immunological correlate for LAIV. However, the relationship between recipient age (or priming status) and serological response varied between vaccine strains. There was a notable increase in HI and MN responses in all cohorts except naive children against the H1N1 strain, where most recipients had responses below the protective antibody threshold. NAI responses were generally weak in naive children against all vaccine strains compared with adults or antigen-primed children. Post-vaccination antibody avidity increased only in primed children below nine years of age against the A/H1N1 strain. Overall, our findings indicate that LAIV elicits functional and neutralizing antibody responses in both naive and antigen experienced cohorts, however, the magnitude and kinetics of the response varies between vaccine strains.

Background Immunity to Streptococcus pyogenes in high burden settings is poorly understood. We explored S. pyogenes nasopharyngeal colonization after intranasal live attenuated influenza vaccine (LAIV) among Gambian children aged 24–59 months, and resulting serological response to 7 antigens. Methods A post hoc analysis was performed in 320 children randomized to receive LAIV at baseline (LAIV group) or not (control). S. pyogenes colonization was determined by quantitative polymerase chain reaction (qPCR) on nasopharyngeal swabs from baseline (day 0), day 7, and day 21. Anti-streptococcal IgG was quantified, including a subset with paired serum before/after S. pyogenes acquisition. Results The point prevalence of S. pyogenes colonization was 7%–13%. In children negative at day 0, S. pyogenes was detected at day 7 or 21 in 18% of LAIV group and 11% of control group participants (P =.12). The odds ratio (OR) for colonization over time was significantly increased in the LAIV group (day 21 vs day 0 OR, 3.18; P =.003) but not in the control group (OR, 0.86; P =.79). The highest IgG increases following asymptomatic colonization were seen for M1 and SpyCEP proteins. Conclusions Asymptomatic S. pyogenes colonization appears modestly increased by LAIV, and may be immunologically significant. LAIV could be used to study influenza- S. pyogenes interactions. Clinical Trials Registration. NCT02972957. [ABSTRACT FROM AUTHOR]

Background: We present post‐vaccination nasal shedding findings from the phase IV, community‐based, triple‐blinded RCT conducted to assess efficacy of trivalent LAIV and inactivated influenza vaccines in rural north India. Methods: Children aged 2–10 years received LAIV or intranasal placebo across 2015 and 2016, as per initial allocation. On days 2 and 4 post‐vaccination, trained study nurses collected nasal swabs from randomly selected subset of trial participants based on operational feasibility, accounting for 10.0% and 11.4% of enrolled participants in 2015 and 2016, respectively. Swabs were collected in viral transport medium and transported under cold chain to laboratory for testing by reverse transcriptase real‐time polymerase chain reaction. Results: In year 1, on day 2 post‐vaccination, 71.2% (74/104) of LAIV recipients shed at least one of vaccine virus strains compared to 42.3% (44/104) on day 4. During year 1, on day 2 post‐vaccination, LAIV‐A(H1N1)pdm09 was detected in nasal swabs of 12% LAIV recipients, LAIV‐A(H3N2) in 41%, and LAIV‐B in 59%. In year 2, virus shedding was substantially lower; 29.6% (32/108) of LAIV recipients shed one of the vaccine virus strains on day 2 compared to 21.3% on day 4 (23/108). Conclusion: At day 2 post‐vaccination in year 1, two‐thirds of LAIV recipients were shedding vaccine viruses. Shedding of vaccine viruses varied between strains and was lower in year 2. More research is needed to determine the reason for lower virus shedding and vaccine efficacy for LAIV‐A(H1N1)pdm09. [ABSTRACT FROM AUTHOR]

• This study highlights an effective intervention to improve vaccine uptake and reduce inequities. • To our knowledge, it is the first intervention study to examine provision of live attenuated influenza vaccine in a nursery school setting. • The study utilises a novel data linkage approach for evaluation of a mixed service delivery model, in the absence of a central universal register. • This study led to a change evidence-based policy change in vaccination service delivery. The schools-based influenza vaccination programme has seen consistently high uptake in Wales, however coverage in pre-school two and three-year olds is lower. One health board area (Cwm Taf University Health Board (UHB)) developed an intervention to offer live attenuated influenza vaccine (LAIV) for three-year olds attending nursery schools alongside the existing general practice (GP) programme. During the pilot, sessions were delivered by health visitors, working with school nurses. The mixed delivery model led to vaccination data being recorded in two separate data systems. To evaluate the impact of the pilot on overall vaccine uptake, data linkage was carried out within the Secure Anonymised Information Linkage (SAIL) Databank. Overall influenza vaccine uptake was calculated for each health board in Wales for two and three-year olds for the 2015–16, 2016–17, and 2017–18 influenza programmes. Uptake in two-year olds in Cwm Taf UHB and also uptake in three-year olds in other health boards in Wales were the comparison groups. Uptake of influenza vaccine in the 2015–16 (pre-intervention) period was 41.0% for three-year olds in Cwm Taf UHB. Following the intervention, coverage increased to 70.7% and 71.5% for 2016–17 and 2017–18 respectively. The same increases in uptake were not seen in two-year olds in Cwm Taf UHB or in three-year olds in non-intervention health boards. In Cwm Taf UHB resident three-year olds in 2015–16 there was an inequality gap in the uptake of 17.4 percentage points between the most and least deprived areas. Uptake increased across all deprivation quintiles in 2016–17 and 2017–18; and the inequality gap decreased to 10.3 and 13.4 percentage points respectively. Influenza vaccination uptake and equality of uptake in three-year olds can be improved by adopting a mixed delivery model across nursery school based immunisation sessions with the additional option of influenza vaccination at GPs. [ABSTRACT FROM AUTHOR]

Background: Influenza viruses continue to cause a significant social and economic burden globally. Vaccination is recognized as the most effective measure to control influenza. Live attenuated influenza vaccines (LAIVs) are an effective means of preventing influenza, especially among children. A reverse genetics (RG) system is required to rapidly update the antigenic composition of vaccines, as well as to design LAIVs with a broader spectrum of protection. Such a system has been developed for the Russian LAIVs only for type A strains, but not for influenza B viruses (IBV). Methods: All genes of the B/USSR/60/69 master donor virus (B60) were cloned into RG plasmids, and the engineered B60, as well as a panel of IBV LAIV reassortants were rescued from plasmid DNAs encoding all viral genes. The engineered viruses were evaluated in vitro and in a mouse model. Results: The B60 RG system was successfully developed, which made it possible to rescue LAIV reassortants with the desired antigenic composition, including hybrid strains with hemagglutinin and neuraminidase genes belonging to the viruses from different IBV lineages. The LAIV candidate carrying the HA of the B/Victoria-lineage virus and NA from the B/Yamagata-lineage virus demonstrated optimal characteristics in terms of safety, immunogenicity and cross-protection, prompting its further assessment as a broadly protective component of trivalent LAIV. Conclusions: The new RG system for B60 MDV allowed the rapid generation of type B LAIV reassortants with desired genome compositions. The generation of hybrid LAIV reassortants with HA and NA genes belonging to the opposite IBV lineages is a promising approach for the development of IBV vaccines with broad cross-protection.

Current seasonal influenza vaccines have suboptimal effectiveness, especially in seasons dominated by viruses that do not match the vaccine. Therefore, finding new approaches to improve the immunogenicity and efficacy of traditional influenza vaccines is of high priority for public health. Licensed live attenuated influenza vaccine (LAIV) is a promising platform for designing broadly protective vaccines due to its ability to induce cross-reactive T-cell immunity. In this study, we tested the hypothesis that truncation of the nonstructural protein 1 (NS1) and the replacement of the nucleoprotein (NP) of the A/Leningrad/17 master donor virus with a recent NP, i.e., switching to 5:3 genome composition, could improve the cross-protective potential of the LAIV virus. We generated a panel of LAIV candidates differing from the classical vaccine by the source of NP gene and/or by the length of NS1 protein. We showed that NS1-modified LAIV viruses had reduced viral replication in the respiratory tract of mice, indicating a more attenuated phenotype compared to the LAIVs with full-length NS1. Most importantly, the LAIV candidate with both NP and NS genes modified induced a robust systemic and lung-localized memory CD8 T-cell response targeting more recent viruses, and better protected immunized mice against lethal challenge with a heterosubtypic influenza virus than the control LAIV variant. Overall, these data indicate that the 5:3 LAIVs with truncated NS1 may be beneficial for protection against heterologous influenza viruses and warrant further preclinical and clinical development. [ABSTRACT FROM AUTHOR]

Live attenuated influenza vaccines offer broader and longer-lasting protection in comparison to inactivated influenza vaccines. The neuraminidase (NA) surface glycoprotein of influenza A virus is essential for the release and spread of progeny viral particles from infected cells. In this study, we de novo synthesized the NA gene, in which 62% of codons were synonymously changed based on mammalian codon bias usage. The codon-reprogrammed NA (repNA) gene failed to be packaged into the viral genome, which was achievable with partial restoration of wild-type NA sequence nucleotides at the 3′ and 5′ termini. Among a series of rescued recombinant viruses, we selected 20/13repNA, which contained 20 and 13 nucleotides of wild-type NA at the 3′ and 5′ termini of repNA, respectively, and evaluated its potential as a live attenuated influenza vaccine. The 20/13repNA is highly attenuated in mice, and the calculated LD50 was about 10,000-fold higher than that of the wild-type (WT) virus. Intranasal inoculation of the 20/13repNA virus in mice induced viral-specific humoral, cell-mediated, and mucosal immune responses. Mice vaccinated with the 20/13repNA virus were protected from the lethal challenge of both homologous and heterologous viruses. This strategy may provide a new method for the development of live, attenuated influenza vaccines for a better and more rapid response to influenza threats. [ABSTRACT FROM AUTHOR]

Seasonal influenza epidemics cause significant pediatric mortality and morbidity worldwide. Live attenuated influenza vaccines (LAIVs) can be administered intranasally, induce a broad and robust immune response, demonstrate higher yields during manufacturing as compared to inactivated influenza vaccines (IIVs), and thereby represent an attractive possibility for young children in developing countries. We summarize recent pediatric studies evaluating LAIV efficacy in developing countries where a large proportion of the influenza-virus-associated respiratory disease burden occurs. Recently, two randomized controlled trials (RCTs) assessing Russian-backbone trivalent LAIV in children reported contradictory results; vaccine efficacy varied between Bangladesh (41 %) and Senegal (0.0 %) against all influenza viral strains. Prior to 2013, Ann Arbor-based LAIV demonstrated superior efficacy as compared to IIV. However, due to low effectiveness of the Ann Arbor-based LAIV against influenza A(H1N1)pdm09-like viruses, the CDC Advisory Committee on Immunization Practices (ACIP) recommended against the use of LAIV during the 2016–17 and 2017–18 influenza seasons. Reduced replicative fitness of the A(H1N1)pdm09 LAIV strains is thought to have led to the low effectiveness of the Ann-Arbor-based LAIV. Once the A(H1N1)pdm09 component was updated, the ACIP reintroduced the Ann-Arbor-based LAIV as a vaccine choice for the 2018–19 influenza season. In 2021, results from a 2-year RCT evaluating the Russian-backbone trivalent LAIV in rural north India reported that LAIV demonstrated significantly lower efficacy compared to IIV, but in Year 2, the vaccine efficacy for LAIV and IIV was comparable. A profounder understanding of the mechanisms underlying varied efficacy of LAIV in developing countries is warranted. Assessing replicative fitness, in addition to antigenicity, when selecting annual A(H1N1)pdm09 components in the Russian-backbone trivalent LAIVs is essential and may ultimately, enable widespread utility in resource-poor settings. [ABSTRACT FROM AUTHOR]

Vasovagal syncope, or fainting, can be triggered by various stimuli, including medical procedures. Syncope after vaccination has been reported, most commonly among adolescents, and can result in injuries. Using the Vaccine Adverse Event Reporting System (VAERS), we reviewed and summarized reports of syncope after live attenuated influenza vaccine, intranasal (LAIV) administered as the sole vaccine (i.e., no concomitant injections). From June 17, 2003 (date of LAIV licensure in the US) through May 31, 2024, VAERS received 50 reports of syncope after LAIV. Nearly half (23; 46 %) pertained to individuals 10–19 years of age. While the vast majority of reports (35; 70 %) did not describe any injuries, 15 people (30 %) were injured, most commonly by falling and hitting their head or face. Twenty-two people (44 %) required evaluation in the emergency department or doctor's office, including an individual who lost consciousness while he was driving home from the vaccination appointment. He did not report any injuries, but the car was severely damaged. Nearly three-quarters of people (37; 74 %) developed syncope within 15 min after vaccination, but fewer than half of reports (24; 48 %) stated that the patient had waited in the observation area for at 15 min. Based on approximately 111.9 million doses of LAIV distributed in the US during the same time period, the reporting rate is approximately 0.4 per million doses, suggesting that syncope following LAIV is rare. The information summarized here may enable clinicians, patients, and caregivers to make a more informed decision regarding preventing injuries that may occur following LAIV-related syncope. [ABSTRACT FROM AUTHOR]

Defective interfering particles (DIPs) are particles containing defective viral genomes (DVGs) generated during viral replication. DIPs have been found in various RNA viruses, especially in influenza viruses. Evidence indicates that DIPs interfere with the replication and encapsulation of wild-type viruses, namely standard viruses (STVs) that contain full-length viral genomes. DIPs may also activate the innate immune response by stimulating interferon synthesis. In this review, the underlying generation mechanisms and characteristics of influenza virus DIPs are summarized. We also discuss the potential impact of DIPs on the immunogenicity of live attenuated influenza vaccines (LAIVs) and development of influenza vaccines based on NS1 gene-defective DIPs. Finally, we review the antiviral strategies based on influenza virus DIPs that have been used against both influenza virus and SARS-CoV-2. This review provides systematic insights into the theory and application of influenza virus DIPs. [ABSTRACT FROM AUTHOR]

This study was a randomized, double-blind, placebo-controlled study to evaluate the safety and viral shedding of live attenuated influenza vaccine (LAIV) in Chinese healthy juveniles and adults. A total of 80 Eligible volunteers were divided into two age groups (≥18 and 3–17 years old). Volunteers were randomly and equally assigned to the experimental group and placebo-controlled group by ratio of 3:1 in each age group. Vaccination was carried out in steps. Totally, 34 (56.67%) adverse events and 24 (40.00%) adverse reactions of the LAIV group were reported. Most adverse reactions were grade 1 and grade 2, and the incidence of adverse reactions that grade 3 was 5%. The most common local reaction was runny nose/nasal congestion (n = 4, 6.67%). And the most common general reaction was fever (n = 10, 16.67%). There were no statistically significant differences in the incidence of total adverse reactions, different grades of adverse reactions, and symptoms between the experimental group and placebo-controlled group. No severe adverse events were reported. Three subjects (5.00%) had been detected vaccine strains on the 3rd day after LAIV vaccination; one was type B and the other two were H3N2. Four subjects (6.67%) had been detected with vaccine strains on the 7th day after LAIV vaccination, all were H3N2. There were no subjects detected carrying the influenza virus on the 15th day after vaccination. There were no statistically significant differences in the positive rate of vaccine strains of influenza virus between the experimental group and placebo-controlled group. The vaccine was well tolerated and not associated with increased rates in adverse reactions or the occurrence of severe adverse events. Pathogenicity of shed vaccine virus to surrounding people was not observed. Thus, Phase Ⅱ study can be carried out as scheduled. [ABSTRACT FROM AUTHOR]

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.

The COVID-19 pandemic emerged in 2020 and has caused an unprecedented burden to all countries in the world. SARS-CoV-2 continues to circulate and antigenically evolve, enabling multiple reinfections. To address the issue of the virus antigenic variability, T cell-based vaccines are being developed, which are directed to more conserved viral epitopes. We used live attenuated influenza vaccine (LAIV) virus vector to generate recombinant influenza viruses expressing various T-cell epitopes of SARS-CoV-2 from either neuraminidase (NA) or non-structural (NS1) genes, via the P2A self-cleavage site. Intranasal immunization of human leukocyte antigen-A*0201 (HLA-A2.1) transgenic mice with these recombinant viruses did not result in significant SARS-CoV-2-specific T-cell responses, due to the immunodominance of NP366 influenza T-cell epitope. However, side-by-side stimulation of peripheral blood mononuclear cells (PBMCs) of COVID-19 convalescents with recombinant viruses and LAIV vector demonstrated activation of memory T cells in samples stimulated with LAIV/SARS-CoV-2, but not LAIV alone. Hamsters immunized with a selected LAIV/SARS-CoV-2 prototype were protected against challenge with influenza virus and a high dose of SARS-CoV-2 of Wuhan and Delta lineages, which was confirmed by reduced weight loss, milder clinical symptoms and less pronounced histopathological signs of SARS-CoV-2 infection in the lungs, compared to LAIV- and mock-immunized animals. Overall, LAIV is a promising platform for the development of a bivalent vaccine against influenza and SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Influenza is still a frequent seasonal infection of the upper respiratory tract, which may have deadly consequences, especially for the elderly. This is in spite of the availability of vaccines suggested for persons above 65 years of age. Two types of conventional influenza vaccines are currently licensed for use—live attenuated and inactivated vaccines. Depending on local regulatory requirements, live attenuated vaccines are produced by the reverse genetics technique or by classical reassortment in embryonated chicken eggs. Sometimes, the efficiency of classical reassortment is complicated by certain properties of the wild-type parent virus. Cases of low efficacy of vaccines have been noted, which, among other reasons, may be associated with suboptimal properties of the wild-type parent virus that are not considered when recommendations for influenza vaccine composition are made. Unfortunately, knowledge surrounding the roles of properties of the circulating influenza virus and its impact on the efficacy of the reassortment process, vaccination efficiency, the infectivity of the vaccine candidates, etc., is now scattered in different publications. This review summarizes the main features of the influenza virus that may dramatically affect different aspects of the preparation of egg-derived live attenuated vaccine candidates and their effectiveness. The author expresses her personal view, which may not coincide with the opinion of other experts in the field of influenza vaccines. [ABSTRACT FROM AUTHOR]

Cocirculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses could pose unpredictable risks to health systems globally, with recent studies suggesting more severe disease outcomes in coinfected patients. The initial lack of a readily available coronavirus disease 2019 (COVID-19) vaccine has reinforced the importance of influenza vaccine programs during the COVID-19 pandemic. Live attenuated influenza vaccine (LAIV) is an important tool in protecting against influenza, particularly in children. However, it is unknown whether LAIV administration influences the outcomes of acute SARS-CoV-2 infection or disease. To investigate this, quadrivalent LAIV was administered to ferrets 3 days before or after SARS-CoV-2 infection. LAIV administration did not exacerbate the SARS-CoV-2 disease course or lung pathology with either regimen. In addition, LAIV administered before SARS-CoV-2 infection significantly reduced SARS-CoV-2 replication and shedding in the upper respiratory tract. This study demonstrated that LAIV administration in close proximity to SARS-CoV-2 infection does not exacerbate mild disease and can reduce SARS-CoV-2 shedding. [ABSTRACT FROM AUTHOR]

Background: In the 2016/2017 influenza season, England was in its fourth season of the roll‐out of a live‐attenuated influenza vaccine (LAIV) targeted at healthy children aged two to less than 17 years. For the first time, all healthy children aged 2 to 8 years were offered LAIV at national level in 2016/2017. Since the commencement of the programme in 2013/2014, a series of geographically discrete pilot areas have been in place where quadrivalent LAIV was also offered to all school age children. In 2016/2017, these were children aged 8 to 11 years, other than those targeted by the national programme. Methods: We evaluated the overall and indirect impact of vaccinating primary school age children, on the population of England, by measuring vaccine uptake levels and comparing cumulative disease incidence through various influenza surveillance schemes, in targeted and non‐targeted age groups in pilot and non‐pilot areas in 2016/2017. Results: Our findings indicate that cumulative primary care influenza‐like consultations, primary and secondary care swab positivity, influenza confirmed hospitalisations and emergency department attendances in pilot areas were overall lower than those observed in non‐pilot areas; however, significant differences were not always observed in both targeted and non‐targeted age groups. Excess mortality was higher in pilot areas compared with non‐pilot areas. Conclusions: These results are similar to earlier seasons of the programme indicating the importance and continuing support of vaccinating all primary school children with LAIV to reduce influenza related illness across the population, although further work is needed to understand the differences in excess mortality. [ABSTRACT FROM AUTHOR]

Current seasonal influenza vaccines have suboptimal effectiveness, especially in seasons dominated by viruses that do not match the vaccine. Therefore, finding new approaches to improve the immunogenicity and efficacy of traditional influenza vaccines is of high priority for public health. Licensed live attenuated influenza vaccine (LAIV) is a promising platform for designing broadly protective vaccines due to its ability to induce cross-reactive T-cell immunity. In this study, we tested the hypothesis that truncation of the nonstructural protein 1 (NS1) and the replacement of the nucleoprotein (NP) of the A/Leningrad/17 master donor virus with a recent NP, i.e., switching to 5:3 genome composition, could improve the cross-protective potential of the LAIV virus. We generated a panel of LAIV candidates differing from the classical vaccine by the source of NP gene and/or by the length of NS1 protein. We showed that NS1-modified LAIV viruses had reduced viral replication in the respiratory tract of mice, indicating a more attenuated phenotype compared to the LAIVs with full-length NS1. Most importantly, the LAIV candidate with both NP and NS genes modified induced a robust systemic and lung-localized memory CD8 T-cell response targeting more recent viruses, and better protected immunized mice against lethal challenge with a heterosubtypic influenza virus than the control LAIV variant. Overall, these data indicate that the 5:3 LAIVs with truncated NS1 may be beneficial for protection against heterologous influenza viruses and warrant further preclinical and clinical development.

Live attenuated influenza vaccines offer broader and longer-lasting protection in comparison to inactivated influenza vaccines. The neuraminidase (NA) surface glycoprotein of influenza A virus is essential for the release and spread of progeny viral particles from infected cells. In this study, we de novo synthesized the NA gene, in which 62% of codons were synonymously changed based on mammalian codon bias usage. The codon-reprogrammed NA (repNA) gene failed to be packaged into the viral genome, which was achievable with partial restoration of wild-type NA sequence nucleotides at the 3′ and 5′ termini. Among a series of rescued recombinant viruses, we selected 20/13repNA, which contained 20 and 13 nucleotides of wild-type NA at the 3′ and 5′ termini of repNA, respectively, and evaluated its potential as a live attenuated influenza vaccine. The 20/13repNA is highly attenuated in mice, and the calculated LD50 was about 10,000-fold higher than that of the wild-type (WT) virus. Intranasal inoculation of the 20/13repNA virus in mice induced viral-specific humoral, cell-mediated, and mucosal immune responses. Mice vaccinated with the 20/13repNA virus were protected from the lethal challenge of both homologous and heterologous viruses. This strategy may provide a new method for the development of live, attenuated influenza vaccines for a better and more rapid response to influenza threats.

• Influenza defective viral genomes can be measured using RT-dPCR. • LAIV replication in human cells is not limited by defective viral genomes. • Defective viral genome packaging is influenced by HA and NA genes. • LAIV vaccine effectiveness is not affected by defective viral genomes. In the 2013–2014 and 2015–2016 seasons, quadrivalent live attenuated influenza vaccine (LAIV) showed reduced pandemic 2009 H1N1 (A/H1N1pdm09) vaccine effectiveness (VE) in the U.S. Impaired fitness of A/H1N1pdm09 LAIV strains in primary human nasal epithelial cells (hNEC) was subsequently shown to be associated with reduced VE. As defective viral genes (DVG) have been detected in QLAIV, it was hypothesised that these might play a role in reduced A/H1N1pdm09 fitness. By applying RT-PCR based approaches, DVG for PB2 , PB1 and PA segments were detected in all influenza A LAIV strains tested. Absolute quantification of PA vRNA as a biomarker, using a novel digital RT-PCR assay (RT-dPCR), showed that DVG were a minority population (between 10.2 and 27.8 % of PA vRNA) in LAIV, irrespective of subtype or VE. Importantly, no difference was observed between the fitter pre-2009 H1N1 A/New Caledonia/20/1999 (A/NC99) and less fit A/H1N1pdm09 A/Bolivia/509/2013 (A/BOL13), containing medians of 16.0 % and 10.2 % PA DVG, respectively. Manipulating propagation conditions and minimising A/BOL13 PA DVG to 5.2 % failed to improve viral replication in hNEC, suggesting DVG were not limiting A/BOL13 fitness. Conversely, DVG were able to reduce A/NC99 replication in hNEC to A/BOL13-like levels, but only by enrichment of PA DVG to 66.5 % of vRNA. Notably, this required LAIV propagation under conditions markedly different to those used for vaccine production. We conclude from these data that abundance of DVG in QLAIV is not associated with variations in influenza A VE and that the reduced fitness of A/BOL13 previously described was not driven by the presence of DVG. [ABSTRACT FROM AUTHOR]

Vaccines are a key part of the global strategy to tackle antimicrobial resistance (AMR) since prevention of infection should reduce antibiotic use. England commenced national rollout of a live attenuated influenza vaccine (LAIV) programme for children aged 2–3 years together with a series of geographically discrete pilot areas for primary school age children in 2013 extending to older children in subsequent seasons. We investigated vaccine programme impact on community antibiotic prescribing rates. Antibiotic prescribing incidence rates for respiratory (RTI) and urinary tract infections (UTI; controls) were calculated at general practice (GP) level by age category (children<=10 years/adults) and season for LAIV pilot and non-pilot areas between 2013/14 and 2015/16. To estimate the LAIV (primary school age children only) intervention effect, a random effects model was fitted. A multivariable random-effects Poisson regression investigated the association of antibiotic prescribing rates in children with LAIV uptake (2–3-year-olds only) at GP practice level. RTI antibiotic prescribing rates for children <=10 years and adults showed clear seasonal trends and were lower in LAIV-pilot and non-pilot areas after the introduction of the LAIV programme in 2013. The reductions for RTI prescriptions (children) were similar (within 3%) in all areas, which coincided with the start the UK AMR strategy. Antibiotic prescribing was significantly (p < 0.0001) related to LAIV uptake in 2–3-year-olds with antibiotic prescribing reduced by 2.7% (95% CI: 2.1% to 3.4%) for every 10% increase in uptake. We found no evidence the LAIV programme for primary school age children resulted in reductions in RTI antibiotic prescribing, however we detected a significant inverse association between increased vaccine uptake in pre-school age children and antibiotic prescribing at GP level. The temporal association of reduced RTI and UTI antibiotic prescribing with the launch of the UK's AMR Strategy in 2013 highlights the importance of a multifaceted approach to tackle AMR. [ABSTRACT FROM AUTHOR]

Introduction: Influenza can be a significant public health problem. Nevertheless, it is preventable through vaccination. Concerning the pediatric population, the recommendation of influenza vaccination is under-represented in many European countries. The aim of this systematic review is to evaluate the cost-effectiveness of universal childhood vaccination against influenza in Europe. Areas covered: We conducted a systematic review of original article assessing the cost-effectiveness of influenza vaccination by searching PubMed, Embase and Scopus databases for studies in English, starting from January 1st, 2010 up to October 21st, 2020. Expert opinion: Our literature review showed that all studies identified highlight that pediatric vaccinations using a live vaccine, especially in the quadrivalent formulation, are cost-effective compared to current vaccinations (elderly and at-risk groups) with TIV or no vaccination. A significant contribution to this positive economic profile is due to the indirect protection. Already many clinical data report the relevant direct and indirect impact of vaccination against influenza for younger subjects. The recent studies collected in this review showed also that the pediatric vaccination is also cost-effective. Therefore, decision-makers should now consider this new favorable evidence. [ABSTRACT FROM AUTHOR]

Introduction: The global co-circulation of two influenza B virus genetic lineages known as B/Yamagata and B/Victoria may lead to a mismatch between the circulating virus and the strain recommended for use in influenza vaccines. Little is known about the protective efficacy of unmatched influenza B strains, especially when it comes to live attenuated influenza vaccine. The main purpose of this study was to demonstrate the viability of using live attenuated influenza vaccine developed on B/USSR/60/69 backbone to protect from heterologous influenza B challenge infection. Methods: To estimate the potential cross-protective activity of mono- and trivalent live attenuated vaccines based on B/Victoria or B/Yamagata genetic lineage virus against a heterological challenge. Ferrets were given one dose of vaccine and then challenged with influenza B virus and monitored for clinical signs associated with influenza infection. Samples of the ferrets’ airways were tested for the presence of challenge virus. Results: Mono- and trivalent live attenuated influenza vaccines were shown to be safe and cross-protective against genetically different influenza B viruses based on virological and histological data and clinical signs. A lower titer of heterologous challenge virus in the airways of vaccinated ferrets compared to mock-vaccinated animals inoculated with challenge virus was detected. Interestingly, B/Victoria-based vaccines were more cross-protective compared with B/Yamagata-based vaccines. Conclusion: In the case of mismatches of B component of the trivalent live attenuated influenza vaccine and lineage of the circulating influenza B viruses, one of the options could be using trivalent preparation containing a B/Victoria lineage component.

Avian influenza A (H1N1) in humans is characterized by severe clinical manifestation and high mortality. The main drawback of current human H5N1 vaccines is related to low immunogenicity. Prime-boost vaccination is considered as an effective approach to enhance vaccine immunogenicity. The aim of this study was to compare immune response and protective efficacy of diverse prime-boost immunization protocols: 1) prime and boost with live influenza vaccine (LAIV) А/17/Turkey/Turkey/05/133 (H5N2); 2) prime with LAIV А/17/Turkey/Turkey/05/133 (H5N2) followed by boost with inactivated influenza vaccine (IIV) “Orniflu” (H5N1). Both vaccination protocols were found to increase serum antibody level against homologous and heterologous influenza A virus strains. In particular, serum HAI antibodies were significantly elevated solely after LAIV/LAIV vaccination. A more sensitive sandwich ELISA assay revealed that serum virus-specific IgG antibody levels were significantly increased after both vaccination protocols as well as after a single LAIV or IIV vaccination. Both LAIV and IIV boost increased titers of serum IgG specific against unrelated influenza A (H5N1) strains: homologous A/NIBRG-23 (clade 2.2), A/Indonesia (clade 2.1) and, to a lesser extent, against clade 1 virus A/ Vietnam and even against heterologous А/New York (H1N1). Single LAIV vaccination was also able to induce antibody responses against all strains examined, though to a lesser degree as compared with either prime-boost protocols. However, amount of splenic CD8+ Тcells specific to homologous influenza A virus strain was solely observed after LAIV/IIV vaccination. Moreover, both LAIV and IIV boosting effect demonstrated high protection level against lethal challenge with А (H1N1) WT virus and significantly decreased lung viral titer compared to control group. Furthermore, both regimens resulted in lung virus clearance after non-lethal challenge with clade 1, 2.1 or 2.2 influenza А (H5N1). In conclusion, we demonstrated that both LAIV/LAIV and LAIV/IIV regimens were able to induce cross-clade A (H5N1) response and that prime-boost immunization was a promising approach to improve immunogenicity of influenza A (H5N1) virus vaccine.

The COVID-19 pandemic emerged in 2020 and has caused an unprecedented burden to all countries in the world. SARS-CoV-2 continues to circulate and antigenically evolve, enabling multiple reinfections. To address the issue of the virus antigenic variability, T cell-based vaccines are being developed, which are directed to more conserved viral epitopes. We used live attenuated influenza vaccine (LAIV) virus vector to generate recombinant influenza viruses expressing various T-cell epitopes of SARS-CoV-2 from either neuraminidase (NA) or non-structural (NS1) genes, via the P2A self-cleavage site. Intranasal immunization of human leukocyte antigen-A*0201 (HLA-A2.1) transgenic mice with these recombinant viruses did not result in significant SARS-CoV-2-specific T-cell responses, due to the immunodominance of NP366 influenza T-cell epitope. However, side-by-side stimulation of peripheral blood mononuclear cells (PBMCs) of COVID-19 convalescents with recombinant viruses and LAIV vector demonstrated activation of memory T cells in samples stimulated with LAIV/SARS-CoV-2, but not LAIV alone. Hamsters immunized with a selected LAIV/SARS-CoV-2 prototype were protected against challenge with influenza virus and a high dose of SARS-CoV-2 of Wuhan and Delta lineages, which was confirmed by reduced weight loss, milder clinical symptoms and less pronounced histopathological signs of SARS-CoV-2 infection in the lungs, compared to LAIV- and mock-immunized animals. Overall, LAIV is a promising platform for the development of a bivalent vaccine against influenza and SARS-CoV-2.

Asthma is one of the most common chronic respiratory conditions worldwide and can be exacerbated by influenza. Findings from early trials demonstrated a higher risk of medically significant wheezing in otherwise healthy young children (aged 6 − 23 months) following administration of the Ann Arbor-backbone live attenuated influenza vaccine (LAIV-AA). In more recent years, several additional studies have investigated the safety of LAIV-AA in older children (2 − 17 years of age) and adults with asthma or prior wheezing, but these findings have not yet been systematically evaluated. We conducted a systematic literature review to assess and synthesize the evidence from all available studies on the safety of LAIV-AA in people aged 2 − 49 years with a diagnosis of asthma or recurrent wheezing. Fourteen studies over 20 years, involving a total of 1.2 million participants, provided evidence that LAIV-AA was well tolerated with no safety concerns in individuals aged 2 − 49 years with a diagnosis of asthma or recurrent wheezing. These data can help inform guidelines for use of LAIV-AA in children and adults with a history of asthma or recurrent wheezing. [ABSTRACT FROM AUTHOR]

Background: There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged ≥ 65 years and for those aged

Influenza is a common disease and in children it can be severe enough to lead to hospitalization and death. Protection of all children against influenza, particularly the youngest, is strongly recommended by most health authorities. However, available vaccines cannot be used in the first 6 months of age, a period of life characterized by the highest risk of influenza-related complications. Maternal immunization is an attractive possibility to overcome this problem. For years, protection against influenza has been pursued by administering the trivalent inactivated vaccine given intramuscularly (IIV3). More recently, a trivalent live attenuated influenza vaccine (LAIV3) administered intranasally was licensed and adopted in a number of countries as an alternative to IIV3. In recent years, to increase protection and include a second B strain, quadrivalent inactivated (IIV4) and live attenuated vaccines (LAIV4) were prepared and licensed. However, during the 2015–2016 season the effectiveness of LAIVs was debated, and they were withdrawn from the list of recommended influenza vaccines in the USA. This review presents an update on the evidence related to the protection of infants against influenza through maternal immunization and the effectiveness of LAIV. Available data indicates that despite maternal immunization, a number of children have no protective antibody levels at birth, and in the majority of children with antibody protection, it is limited to the first 8 weeks of the postnatal period. Moreover, data on LAIV effectiveness in the pediatric population must be clarified because this vaccine can significantly improve vaccination coverage in children.

• Immunogenicity and efficacy of the MDCK- and egg-based LAIV against viruses of H5 and H7 subtypes was studied in ferrets. • Immunogenicity of the MDCK-based H5 and H7 LAIV was comparable to that of egg-based LAIV. • MDCK- and egg-based LAIV completely inhibited influenza virus replication in the lower respiratory tract. • Two doses of MDCK-based LAIV protected against challenge with heterologous H5N1 heterologous challenge. During a pandemic, the availability of specific pathogen free chicken eggs is a major bottleneck for up-scaling response to the demand for influenza vaccine. This has led us to explore the use of Madin-Darby Canine Kidney (MDCK) cells for the manufacture of live attenuated influenza vaccine (LAIV) that provides production flexibility and speed. The present study reports the comparison of the immunogenicity and efficacy of two MDCK-based LAIVs against two egg-based LAIVs prepared from the same pandemic potential strains of H5 and H7 subtypes after a single dose of the vaccine followed by a challenge with a homologous wild type strain. The vaccine strains have been generated by classical method of reassortment using the A/Leningrad/134/17/57 master donor strain. Additionally, a prime-boost regimen of the MDCK-based vaccine followed by a challenge with a homologous wild type strain for H5 and H7 immunized ferrets and also a heterologous wild type strain for the H5 immunized animals was studied. No difference in the hemagglutination inhibition and virus neutralization antibody titers against the homologous virus was observed following a single dose of either egg-based or MDCK-based H5 and H7 LAIV vaccine. A second dose of MDCK-based vaccine significantly boosted antibody titers in the vaccinated animals. Both a single dose or two doses of LAIV provided complete protection from lower respiratory tract infection and resulted in a significant reduction in the virus titers recovered from the throat, nasal turbinates and lungs after challenge with the homologous wild type strain. Protection from a challenge with a heterologous strain of H5 was also observed after two doses of the MDCK-based LAIVs. This data strongly supports the use of MDCK as a substrate for the manufacture of LAIV which ensures reliable quality, safety, production flexibility, speed and breadth of protection, features that are highly critical during a pandemic. [ABSTRACT FROM AUTHOR]

Background: Annual influenza vaccination is recommended for all individuals six months of age and older, including those with HIV infection. Prior to this statement, the National Advisory Committee on Immunization (NACI) stated that live attenuated influenza vaccine (LAIV) was contraindicated for all individuals with HIV infection. The objective of this article is to update NACI's guidance on the use of LAIV for HIV-infected individuals.Methods: A systematic literature review of the use of LAIV in individuals with HIV was undertaken. The Canadian Adverse Events Following Immunization Surveillance System was searched for reports of adverse events following vaccination with LAIV in HIV-infected individuals. NACI approved the revised recommendations.Results: NACI concluded that LAIV is immunogenic in children with HIV, and available data suggest that it is safe, although data were insufficient to detect possible uncommon adverse effects. LAIV may be considered as an option for vaccination of children 2-17 years old who meet the following criteria: 1) receiving highly active antiretroviral therapy for at least four months; 2) CD4 count of 500/µL or greater if age 2-5 years, or of 200/µL or greater if age 6-17 years; and 3) HIV plasma RNA less than 10,000 copies/mL. LAIV remains contraindicated for adults with HIV because of insufficient data. Intramuscular influenza vaccination is considered the standard for children living with HIV by NACI and the Canadian Paediatric & Perinatal HIV/AIDS Research Group, particularly for those without HIV viral load suppression (i.e. plasma HIV RNA is 40 copies/mL or greater). However, if intramuscular (IM) vaccination is not accepted by the patient or substitute decision-maker, LAIV would be reasonable for children meeting the criteria listed above.Conclusion: LAIV may be considered as an option for annual vaccination of selected children with HIV. [ABSTRACT FROM AUTHOR]

No data on the safety and efficacy of a live attenuated influenza vaccine in China have ever been reported. At a site of a phase 3 randomized, double-blind, placebo-controlled clinical trial in eastern China, eligible healthy children aged 3–17 years underwent randomization to receive live attenuated vaccine or placebo at a ratio of 1:1. The primary objective of the study was the prevention of laboratory-confirmed influenza illness during the surveillance period, starting on day 15 after vaccination. A total of 2000 participants were enrolled, with 998 receiving the vaccine and 1001 receiving placebo. Sixty-four cases of influenza-like illness were observed, of which, 44 were laboratory-confirmed (12 in vaccine group versus 32 in placebo group). Vaccine efficacy was 62.5% (95%CI: 27.6–80.6) against all types of influenza and 63.3% (95%CI: 27.5–81.5) against influenza H3N2 illness. 11 severe adverse events reported (7 in LAIV group versus 4 in placebo group) were all deemed to be non-vaccine-related. Adverse events occurred in 412 (41.3%) participants in the vaccine group versus 389 (38.9%; p = 0.274) participants in the placebo group. Significant increase incidence of fever was observed in participants in the vaccine group, especially in those aged 3–9 years. The live attenuated influenza vaccine showed good efficacy and safety among 3- to 17-year-olds children during the 2016–2017 season at a site in eastern China. Clinical Trial Registry Number: NCT02964065. [ABSTRACT FROM AUTHOR]

Influenza, a common cause of acute respiratory infections, is an important health problem worldwide, including in India. Influenza is associated with several complications; people with comorbidities and the elderly are at a higher risk for such complications. Moreover, the influenza virus constantly changes genetically, thereby worsening therapeutic outcomes. Vaccination is an effective measure for the prevention of influenza. Despite the availability of global guidelines on influenza vaccination in adults, country"specific guidelines based on regional variation in disease burden are required for better disease management in India. With this aim, the Indian Chest Society and National College of Chest Physicians of India jointly conducted an expert meeting in January 2019. The discussion was aimed at delineating evidence"based recommendations on adult influenza vaccination in India. The present article discusses expert recommendations on clinical practice guidelines to be followed in India for adult influenza vaccination, for better management of the disease burden. [ABSTRACT FROM AUTHOR]

The reassortant vaccine strain of live attenuated influenza vaccine inherits temperature sensitivity and areactogenicity from cold-adapted attenuated master donor virus. In Russia, B/ USSR/60/69 master donor virus (B60) is currently in use for the preparation of live attenuated type B influenza vaccine candidates. Trivalent live attenuated influenza vaccine based on A/ Leningrad/134/17/57 and B60 are licensed for the use in Russia for single dose vaccination of adults and children over 3 years. B/Leningrad/14/17/55 (B14) cold-adapted virus is a backup master donor virus for live attenuated type B influenza vaccine. According to our preliminary estimates, it is more attenuated than B60, which can allow expanding applicability of this vaccine for children under 3 years of age. In this paper, the role of B14 genes in its attenuation was assessed. Representative collection of reassortants of B14 with epidemic influenza B viruses was obtained, a phenotypic analysis of reassortants was performed, and their pathogenicity for animals was assessed. The leading role of PB2 and PA genes in attenuation of B14 master donor virus was proven. [ABSTRACT FROM AUTHOR]

• The timing and route of influenza vaccines effect symptom reporting in healthy adults. • Symptoms experienced by healthy adults were further affected by the presence of S. pneumoniae. • LAIV vaccination prior to S. pneumoniae exposure/colonisation led to reduced symptoms. • TIV vaccination prior to S. pneumoniae exposure/colonisation led to increased nasal symptoms compared to LAIV. Nasopharyngeal colonisation by S. pneumoniae is a prerequisite for invasive pneumococcal infections. Influenza co-infection leads to increased susceptibility to secondary pneumonia and mortality during influenza epidemics. Increased bacterial load and impaired immune responses to pneumococcus caused by influenza play a role in this increased susceptibility. Using an Experimental Human Challenge Model and influenza vaccines, we examined symptoms experienced by healthy adults during nasal co-infection with S. pneumoniae and live attenuated influenza virus. Randomised, blinded administration of Live Attenuated Influenza Vaccine (LAIV) or Tetravalent Inactivated Influenza Vaccine (TIV) either preceded bacterial inoculation or followed it, separated by a 3-day interval. The presence and density of S. pneumoniae was determined from nasal washes. Participants completed a symptom questionnaire from the first intervention until 6 days post second intervention. The timing and type of influenza vaccination and presence of S. pneumoniae in the nasopharynx significantly affected symptom reporting. In the study where influenza vaccination preceded bacterial inoculation : nasal symptoms were less common in the LAIV group than the TIV group (OR 0.57, p < 0.01); with colonisation status only affecting the TIV group where more symptoms were reported by colonised participants compared to non-colonised participants following inoculation (n = 12/23 [52.17%] vs n = 13/38 [34.21%], respectively; p < 0.05). In the study where influenza vaccination followed bacterial inoculation : no difference was seen in the symptoms reported between the LAIV and TIV groups following inoculation and subsequent vaccination; and symptoms were unaffected by colonisation status. Symptoms experienced during live viral vaccination and bacterial co-infection in the nasopharynx are directly affected by the precedence of the pathogen acquisition. Symptoms were directly affected by nasal pneumococcal colonisation but only when TIV was given prior to bacterial exposure. [ABSTRACT FROM AUTHOR]

• Live attenuated influenza vaccine H1N1 strain A/Bolivia had reduced effectiveness. • Novel assays identified H1N1 strain with improved replicative fitness (A/Slovenia). • More children shed the A/Slovenia vaccine strain than the A/Bolivia strain. • A/Slovenia strain had improved immunogenicity versus the A/Bolivia strain. • A/Slovenia immune responses comparable to efficacious pre-pandemic H1N1 strain. Quadrivalent live attenuated influenza vaccine (LAIV4) showed reduced effectiveness against the A/H1N1 component in the 2013–2014 and 2015–2016 influenza seasons. The most likely cause of reduced LAIV effectiveness against A(H1N1)pdm09 strains was poor intranasal replication. To compare the immunogenicity and shedding of a new A/H1N1 strain (A/Slovenia), to a A/H1N1 strain known to have reduced effectiveness (A/Bolivia). This was a randomized, double-blind, multicenter study. Children aged 24–<48 months of age were randomized 1:1:1 to receive two doses of LAIV4 2017–2018 (LAIV4 A/Slovenia), or LAIV4 2015–2016 or trivalent LAIV (LAIV3) 2015–2016 formulations (LAIV4 A/Bolivia or LAIV3 A/Bolivia , respectively) on days 1 and 28. The primary endpoint was strain-specific hemagglutination inhibition (HAI) antibody seroresponse at 28 days post each dose, and secondary endpoints included immunogenicity, shedding, and safety. Solicited symptoms, adverse events (AEs), and serious AEs (SAEs) were recorded. Pre-specified statistical testing was limited to the primary endpoint of HAI antibody responses. A total of 200 children were randomized (median age 35.3 months; 53% male; 57% had previously received influenza vaccine). Significantly higher HAI antibody responses for the A/Slovenia strain were observed after Dose 1 and Dose 2. Neutralizing antibodies and nasal immunoglobulin A antibody responses were higher for A/Slovenia versus A/Bolivia. More children shed the A/Slovenia vaccine strain than the A/Bolivia strain on Days 4–7 after Dose 1. No deaths, SAEs, or discontinuations from vaccine occurred. The new A(H1N1)pdm09 A/Slovenia LAIV strain demonstrated improved immunogenicity compared with a previous strain with reduced effectiveness and induced immune responses comparable to a highly efficacious pre-pandemic H1N1 LAIV strain. These results support the use of LAIV4 containing A/Slovenia as a vaccine option in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Live attenuated influenza vaccines (LAIVs) have been in use for more than three decades and are now licensed in many countries. There is evidence that LAIVs can have greater efficacy than inactivated influenza vaccines, especially against mismatched influenza, however, in recent years, a number of trials have found a lack of LAIV efficacy, mainly in relation to the H1N1 virus. Areas covered: In this review, we summarize the results of clinical research published in the past 5 years on the immunogenicity of LAIVs, with special attention to the mechanisms of establishing protective immunity and some factors that may influence immunogenicity and efficacy. Expert opinion: A number of recent clinical studies confirmed that the immune responses to LAIVs are multifaceted, involving different immune mechanisms. These trials suggest that the intrinsic replicative properties of each LAIV component should be taken into account, and the precise effects of adding a fourth vaccine strain to trivalent LAIV formulations are still to be identified. In addition, new data are emerging regarding the impact of pre-vaccination conditions, such as preexisting immunity or concurrent asymptomatic viral and bacterial respiratory infections, on LAIV immunogenicity, suggesting the importance of monitoring them during clinical trials or vaccination campaigns. [ABSTRACT FROM AUTHOR]

The development of an influenza vaccine with broad protection and durability remains an attractive idea due to the high mutation rate of the influenza virus. An extracellular domain of Matrix 2 protein (M2e) is among the most attractive target for the universal influenza vaccine owing to its high conservancy rate. Here, we generated two recombinant live attenuated influenza vaccine (LAIV) candidates encoding four M2e epitopes representing consensus sequences of human, avian and swine influenza viruses, and studied them in a preclinical ferret model. Both LAIV+4M2e viruses induced higher levels of M2e-specific antibodies compared to the control LAIV strain, with the LAIV/HA+4M2e candidate being significantly more immunogenic than the LAIV/NS+4M2e counterpart. A high-dose heterosubtypic influenza virus challenge revealed the highest degree of protection after immunization with LAIV/HA+4M2e strain, followed by the NS-modified LAIV and the classical LAIV virus. Furthermore, only the immune sera from the LAIV/HA+4M2e-immunized ferrets protected mice from a panel of lethal influenza viruses encoding M genes of various origins. These data suggest that the improved cross-protection of the LAIV/HA+4M2e universal influenza vaccine candidate was mediated by the M2e-targeted antibodies. Taking into account the safety profile and improved cross-protective potential, the LAIV/HA+4M2e vaccine warrants its further evaluation in a phase I clinical trial.

There is an unmet public health need for a universal influenza vaccine (UIV) to provide broad and durable protection from influenza virus infections. The identification of broadly protective antibodies and cross-reactive T cells directed to influenza viral targets present a promising prospect for the development of a UIV. Multiple targets for cross-protection have been identified in the stalk and head of hemagglutinin (HA) to develop a UIV. Recently, neuraminidase (NA) has received significant attention as a critical component for increasing the breadth of protection. The HA stalk-based approaches have shown promising results of broader protection in animal studies, and their feasibility in humans are being evaluated in clinical trials. Mucosal immune responses and cross-reactive T cell immunity across influenza A and B viruses intrinsic to live attenuated influenza vaccine (LAIV) have emerged as essential features to be incorporated into a UIV. Complementing the weakness of the stand-alone approaches, prime-boost vaccination combining HA stalk, and LAIV is under clinical evaluation, with the aim to increase the efficacy and broaden the spectrum of protection. Preexisting immunity in humans established by prior exposure to influenza viruses may affect the hierarchy and magnitude of immune responses elicited by an influenza vaccine, limiting the interpretation of preclinical data based on naive animals, necessitating human challenge studies. A consensus is yet to be achieved on the spectrum of protection, efficacy, target population, and duration of protection to define a "universal" vaccine. This review discusses the recent advancements in the development of UIVs, rationales behind cross-protection and vaccine designs, and challenges faced in obtaining balanced protection potency, a wide spectrum of protection, and safety relevant to UIVs. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory disease in young children, elderly and immunocompromised adults. There is no licensed vaccine against RSV although development of an effective and safe RSV vaccine has been a high priority for several decades. Among the various vaccine platforms, the viral-vectored RSV vaccines based on licensed cold-adapted live attenuated influenza vaccine (LAIV) might offer an advantage of inducing adequate mucosal CD8 T cell immunity at the infection site of respiratory pathogens. We constructed two recombinant LAIV viruses expressing immunodominant T-cell epitopes of RSV M2-1 protein. The results in this study provide evidence that RSV CD8 T cell epitopes delivered by LAIV viral vector could confer protection against RSV infection without causing pulmonary eosinophilia and inflammatory RSV disease in mice. In addition, these chimeric LAIV-RSV vaccines retained their attenuated phenotype and ability to protect against virulent influenza virus, thus providing a unique approach to fight against two dangerous respiratory viral pathogens using a single vaccine preparation. • Two recombinant attenuated influenza viruses expressing CD8 T-cell epitopes of RSV M2-1 protein were studied in mice. • The LAIV-RSV vaccines induce functional RSV M2 82 -specific cytotoxic T cell responses. • Intranasal vaccination protects mice against both influenza virus and RSV. • The bivalent vaccines do not induce pulmonary immunopathology after RSV challenge. [ABSTRACT FROM AUTHOR]

During the 2013–2014 influenza season, the quadrivalent live attenuated influenza vaccine (QLAIV), had lower than expected vaccine effectiveness (VE) against circulating A/H1N1pdm09 viruses in the USA. The underlying reason proposed for this was that the A/H1N1pdm09 vaccine strain, A/California/07/2009 (A/CA09), had a thermally unstable haemagglutinin (HA) protein. Consequently, a new A/H1N1pdm09 candidate strain, A/Bolivia/559/2013 (A/BOL13), was developed for inclusion in the 2015–2016 QLAIV. A key parameter for selection of A/BOL13 was its more thermostable HA phenotype compared with A/CA09. During the 2015–2016 season, QLAIV containing A/BOL13 was found in some studies to have improved, but still with suboptimal, VE against circulating A/H1N1pdm09 viruses and was not recommended for use by the CDC in the US market in the 2016–2017 influenza season. This suggested that improved HA thermostability had not entirely resolved the reduced VE observed. One hypothesis for this was that, by improving thermostability, the A/BOL13 HA protein had been over-stabilised, compromising its activation at the low endosomal pH required for successful viral entry. Here we demonstrate that, while the A/BOL13 HA protein is more stable than that of A/CA09, its thermal and pH stability were comparable with historically efficacious LAIV strains, suggesting that the HA had not been over-stabilised. Furthermore, studies simulating potential heat exposure during distribution by exposing QLAIV nasal sprayers to 33 °C for 4 h showed that, while remaining within product specification, A/CA09 viral potency was statistically decreased after 12 weeks at 2–8 °C. These data suggest that although unfavourable HA protein stability may have contributed to the reduced VE of A/CA09 in 2013–2014, it was unlikely to have affected A/BOL13 in 2015–2016. We conclude that HA stability was not the primary cause of the reduced effectiveness of LAIV against A/H1N1pdm09 viruses in the 2013–2014 and 2015–2016 seasons. [ABSTRACT FROM AUTHOR]

Live attenuated influenza vaccine (LAIV) is considered one of the most effective vaccines and can be manufactured quickly and inexpensively to counter seasonal or pandemic influenza. Lyophilization is widely used in vaccine production. However, it requires a longer production cycle and large-scale equipment, thus posing a considerable financial burden for developing countries. A potential solution is the development of liquid LAIV, which can increase the yield and reduce the cost of production. In this study, influential factors of LAIV, such as potential stabilizing excipients and pH, were optimized by an orthogonal design. We found that pH is the most critical factor for the stability of LAIV; salt concentration and initial virus titer are also important for LAIV stability. With these data, we developed a liquid formulation consisting of 2.5% sucrose, 0.1% monosodium glutamate, 1% arginine, and 0.5% human serum albumin, with pH ranging from 6.2 to 6.9 (optimum pH 6.5-6.7), for optimal production of monovalent or trivalent LAIVs. This liquid formulation has the potential to considerably improve vaccine production capacity to compensate for the immense shortfall in influenza vaccines globally. [ABSTRACT FROM AUTHOR]

We studied the constellation of genes encoding polymerase complex proteins of master donor viruses for Russian live attenuated influenza vaccine type B. Reassortants of the reserve attenuation donor B/Leningrad/14/17/55 with B/USSR/60/69 master donor virus currently used for manufacturing seasonal influenza vaccine were prepared and examined. Most reassortants obtained by the classical reassortment method inherited all genes from the B/Leningrad/14/17/55 virus except the gene encoding PB1 subunit of the polymerase complex. One reassortant was selected for further evaluation of the role of PB1 gene. Greater attenuation of the strain for experimental animals (mice) in comparison with the original strains was demonstrated. This indicates high degree of constellation of genes of cold-adapted master donor viruses and the important compensating role of amino acid substitutions in the PB1 protein of B/Leningrad/14/17/55 donor virus in preventing viral hyperattenuation. [ABSTRACT FROM AUTHOR]