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The safety and immunogenicity of the coadministration of an inactivated SARS-CoV-2 vaccine (Sinopharm BBIBP-CorV), quadrivalent split-virion inactivated influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults in China is unknown. In this open-label, non-inferiority, randomised controlled trial, participants aged ≥ 18 years were recruited from the community. Individuals were eligible if they had no history of SARS-CoV-2 vaccine or any pneumonia vaccine and had not received an influenza vaccine during the 2020–21 influenza season. Eligible participants were randomly assigned (1:1:1), using block randomization stratified, to either: SARS-CoV-2 vaccine and IIV4 followed by SARS-CoV-2 vaccine and PPV23 (SARS-CoV-2 + IIV4/PPV23 group); two doses of SARS-CoV-2 vaccine (SARS-CoV-2 vaccine group); or IIV4 followed by PPV23 (IIV4/PPV23 group). Vaccines were administered 28 days apart, with blood samples taken on day 0 and day 28 before vaccination, and on day 56. Between March 10 and March 15, 2021, 1152 participants were recruited and randomly assigned to three groups (384 per group). 1132 participants were included in the per-protocol population (375 in the SARS-CoV-2 + IIV4/PPV23 group, 380 in the SARS-CoV-2 vaccine group, and 377 in the IIV4/PPV23 group). The seroconversion rate (100 % vs 100 %) and GMT (159.13 vs 173.20; GMT ratio of 0.92 [95 % CI 0.83 to 1.02]) of SARS-CoV-2 neutralising antibodies in the SARS-CoV-2 + IIV4/PPV23 group was not inferior to those in the SARS-CoV-2 vaccine group. The SARS-CoV-2 + IIV4/PPV23 group was not inferior to the IIV4/PPV23 group in terms of seroconversion rates and GMT of influenza virus antibodies for all strains except for the seroconversion rate for the B/Yamagata strain. The SARS-CoV-2 + IIV4/PPV23 group was not inferior to the IIV4/PPV23 group regarding seroconversion rates and GMC of Streptococcus pneumoniae IgG antibodies specific to all serotypes. All vaccines were well tolerated. The coadministration of the inactivated SARS-CoV-2 vaccine and IIV4/PPV23 is safe with satisfactory immunogenicity. This study is registered with ClinicalTrials.gov, NCT04790851.

Pathogenic avian influenza A virus H5N1 has caused outbreaks in poultry and migratory birds in Asia, Africa, and Europe, and caused disease and death in people. Although person-to-person spread of current H5N1 strains is unlikely, the virus is a potential source of a future influenza pandemic. Our aim was to assess the safety and immunogenicity of a vaccine against the H5N1 strain. We did a randomised, open-label, non-controlled phase I trial in 300 volunteers aged 18–40 years and assigned one of six inactivated split influenza A/Vietnam/1194/2004 (H5N1) influenza vaccine formulations, comprising 7·5 μg (with adjuvant n=50, without adjuvant n=49), 15 μg (n=50, n=50), or 30 μg (n=51, n=50) of haemagglutinin with or without aluminium hydroxide adjuvant. Individuals received two vaccinations (on days 0 and 21) and provided blood samples (on days 0, 21, and 42) for analysis by haemagglutination inhibition and microneutralisation. We recorded all adverse events. Analyses were descriptive. All formulations were well tolerated, with no serious adverse events, few severe reactions, and no oral temperatures of more than 38°C. All formulations induced an immune response, and responses were detectable in some individuals after only one dose. The adjuvanted 30 μg formulation induced the greatest response (67% haemagglutinin-inhibition seroconversion rate after two vaccinations). Adjuvant did not improve the response to the lower doses. Two vaccinations of non-adjuvanted 7·5 μg, adjuvanted 15 μg, or non-adjuvanted 15 μg seroconverted more than 40% of participants (haemagglutinin-inhibition test only). Haemagglutinin inhibition and neutralising results were comparable. A two-dose regimen with an adjuvanted 30 μg inactivated H5N1 vaccine was safe and showed an immune response consistent with European regulatory requirements for licensure of seasonal influenza vaccine. We noted encouraging responses with lower doses of antigen that need further study to ascertain their relevance for the choice of the final pandemic vaccine.

Background. Antibody titers decrease with time following influenza vaccination, raising concerns that vaccine efficacy might wane. However, the relationship between time since vaccination and protection is unclear. Methods. Time-varying vaccine efficacy (VE[t]) was examined in healthy adult participants (age range, 18-49 years) in a placebo-controlled trial of inactivated influenza vaccine (IIV) and live-attenuated influenza vaccine (LAIV) performed during the 2007-2008 influenza season. Symptomatic respiratory illnesses were laboratory-confirmed as influenza. VE(t) was estimated by fitting a smooth function based on residuals from Cox proportional hazards models. Subjects had blood samples collected immediately prior to vaccination, 30 days after vaccination, and at the end of the influenza season for testing by hemagglutination inhibition and neuraminidase inhibition assays. Results. Overall efficacy was 70% (95% confidence interval [CI], 50%-82%) for IIV and 38% (95% CI.5%-59%) for LAIV. Statistically significant waning was detected for IIV (P = .03) but not LAIV (P = .37); however, IIV remained significantly efficacious until data became sparse at the end of the season. Similarly, antibody titers against influenza virus hemagglutinin and neuraminidase significantly decreased over the season among IIV recipients. Conclusions. Both vaccines were efficacious but LAIV less so. IIV efficacy decreased slowly over time, but the vaccine remained significantly efficacious for the majority of the season.

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.Design Double blind randomised trial.Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza.Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.Registration Clinical Trials NCT00298233

Antibody titers measured by hemagglutination inhibition (HAI) correlate with protection against influenza virus infection and are used to specify criteria for vaccine licensure. In a randomized, controlled trial of seasonal influenza vaccination in 773 children aged 6-17 years, we estimated that HAI titers of 1:40 against A(H1N1) pdm09 and B(Victoria lineage) were associated with 48% (95% confidence interval [CI], 30%-62%) and 55% (95% CI, 32%-70%) protection against PCR-confirmed infection with each strain. Our analysis accounted for waning in antibody titers over time, and could be particularly useful in settings where influenza activity is delayed or prolonged relative to measurement of antibody titers.

Few data exist on the immunogenicity and safety of an inactivated enterovirus 71 vaccine (EV71 vaccine) coadministered with trivalent split-virion inactivated influenza vaccine (IIV3) in infants. This trial was a phase 4, randomized, controlled trial. Infants aged 6-11 months were eligible, with no history of hand, foot and mouth disease (HFMD) and no history of EV71 vaccine or any influenza vaccine. Eligible infants were randomly assigned to EV71+IIV3 group, EV71 group or IIV3 group. Blood samples were collected on day 0 and 56. Between September 2019 and June 2020, 1151 infants met eligibility criteria and 1134 infants were enrolled. 1045 infants were included in the per-protocol population, including 347 in the EV71+IIV3 group, 343 in the EV71 group, and 355 in the IIV3 group. The seroconversion rate (98.56% vs 98.54%; seroconversion rates difference of 0.02% [95% CI: 0.70-0.98]) and GMT (419.05 vs 503.72; GMT ratio of 0.83 [95% CI 0.70 - 0.98]) of EV71 neutralizing antibodies in the EV71+IIV3 group was not inferior to those in the EV71 group. The non-inferiority results for influenza virus antibodies (A/H1N1, A/H3N2 and B) showed that the seroconversion rates and GMTs of the EV71+IIV3 group were non-inferiority to those of the IIV3 group. Systemic and local adverse event rates were similar between groups. None of serious adverse events (SAEs) were related to vaccination. Coadministration of the EV71 vaccine with IIV3 was safe and did not interfere with immunogenicity. These findings support a viable immunization strategy for infants with the EV71 vaccine coadministered with IIV3 in China. This trial is registered with ClinicalTrials.gov, number NCT04091880.

Background. Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. Methods. Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and I l a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine (A/California/07/09 [H1N1], A/Perth/16/09 [H3N2], B/Brisbane/60/08). Results. Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)—numbers significantly lower (P<.001) than shedding after initial LAIV and after IIV-LAIV (P<.001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. Conclusions. LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis. Clinical Trials Registration. NCT01246999.

The HB strain of duck Tembusu virus (DTMUV) propagated in the brains of newborn mice was used to prepare antigens for use in the hemagglutination inhibition (HI) test. Results showed that such prepared antigens are highly specific to the serum samples derived from DTMUV-infected animals. No spurious hemagglutination reactions against serum samples specific to avian influenza virus H5, H7, H9 subtypes, Newcastle disease virus, egg drop syndrome virus, duck plague virus, and duck hepatitis A virus were observed. The HI test can detect specific antibodies in the serum samples as early as day 4 after experimental infection of ducks with DTMUV. When compared to a virus neutralization test, the sensitivity is 100%. Overall, the HI test developed is highly specific to DTMUV and can be used in clinical diagnosis of diseases and in vaccine studies to monitor the kinetics of antibody response.

We developed a recombinant Newcastle disease virus (NDV) LaSota (rLS) expressing the infectious bronchitis virus (IBV) S2 gene (rLS/IBV.S2). The recombinant virus showed somewhat-reduced pathogenicity compared to the parental lentogenic LaSota strain but effectively elicited hemagglutination inhibition antibodies against NDV and protected chickens against lethal challenge with virulent NDV/CA02. IBV heterotypic protection was assessed using a prime-boost approach with a commercially available attenuated IBV Massachusetts (Mass)-type vaccine. Specific-pathogen-free chickens primed ocularly with rLS/IBV.S2 at 4 days of age and boosted with Mass at 18 days of age were completely protected against challenge at 41 days of age with a virulent Ark-type strain. In a second experiment, we compared protection conferred by priming with rLS/IBV.S2 and boosting with Mass (rLS/IBV.S2+Mass) versus priming and boosting with Mass (Mass+Mass). We also modified the timing of vaccination to prime at 1 day of age and boost at 12 days of age. Challenge with virulent Ark was performed at 21 days of age. Based on clinical signs, both vaccinated groups appeared equally protected against challenge compared to unvaccinated challenged chickens. Viral loads in lachrymal fluids of birds receiving rLS/IBV.S2+Mass showed a clear tendency of improved protection compared to Mass+Mass; however, the difference did not achieve statistical significance. A significant difference (P < 0.05) was determined between these groups regarding incidence of detection of challenge IBV RNA in the trachea; viral RNA was detected in 50% of rLS/IBV.S2+Mass-vaccinated chickens while chickens vaccinated with Mass+Mass and unvaccinated challenged controls showed 84 and 90% incidence of IBV RNA detection in the trachea, respectively. These results demonstrate that overexposing the IBV S2 to the chicken immune system by means of a vectored vaccine, followed by boost with whole virus, protects chickens against IBV showing dissimilar S1. El gene S2 del virus de la bronquitis infecciosa expresado en virus recombinantes confiere una amplia protección contra el desafío. Se ha desarrollado un virus recombinante de la enfermedad de Newcastle (NDV) LaSota (rLS) que expresa el gene S2 del virus de la bronquitis infecciosa (IBV) (rLS/IBV.S2). El virus recombinante mostró patogenicidad ligeramente reducida en comparación con la cepa La Sota lentogénica que sirvió de origen, pero indujo efectivamente anticuerpos inhibidores de la hemaglutinación contra el virus de Newcastle y protegió a los pollos contra el desafío letal con la cepa virulenta NDV/CA02. Se evaluó la protección heterotípica contra el virus de bronquitis a través de un enfoque de primovacunación y de refuerzo con una vacuna Massachusetts (Mass) atenuada disponible en el mercado. Pollos libres de patógenos específicos primovacunados ocularmente con el virus rLS/IBV.S2 a los cuatro días de edad y revacunados con la cepa Massachusetts a los 18 días de edad estuvieron completamente protegidos contra la exposición a los 41 días de edad con una cepa virulenta cepa de tipo Ark. En un segundo experimento, se comparó la protección conferida por la primovacunación con rLS/IBV.S2 y la revacunación con Massachusetts (rLS/IBV.S2+Mass) en comparación con la primovacunación y refuerzo con Massachusetts (Mass+Mass). También se modificó el momento de la vacunación para primovacunar al primer día de edad y con refuerzo a los 12 días de edad. El desafío con una cepa Ark virulenta se realizó a los 21 días de edad. Con base en los signos clínicos, los dos grupos vacunados aparecieron igualmente protegidos contra el desafío en comparación con pollos desafiados y no vacunados. La carga viral en los fluidos lacrimales de las aves que recibieron el virus rLS/IBV.S2 +Mass mostraron una clara tendencia de mejor protección en comparación con el esquema Mass+Mass, sin embargo, la diferencia no alcanzó significancia estadística. Se determinó una diferencia significativa (P < 0.05) entre estos grupos con respecto a la incidencia de detección del ARN del virus de bronquitis de desafío en la tráquea; se detectó ARN viral en 50% de los pollos vacunados con rLS/IBV.S2 +Mass mientras que los pollos vacunados con el esquema Mass+Mass y los controles no vacunados y desafiados mostraron una incidencia 84% y 90% en la detección del ARN del virus de la bronquitis infecciosa en la tráquea, respectivamente. Estos resultados demuestran que la sobreexposición del sistema inmune del pollo al gene S2 del virus de bronquitis al mediante una vacuna recombinante, seguido por revacunación con virus completo, protege a los pollos contra virus de bronquitis infecciosa que muestran genes S1 diferentes.

•High-dose trivalent influenza vaccine is licensed for adults ≥65 years of age.•A quadrivalent formulation with antigen from both B lineages has been developed.•Adding the second B strain improved immunogenicity against the added strain.•Immunogenicity against the other strains remained the same.•The vaccine’s tolerability was unaffected by adding the second B strain. A high-dose, split-virion inactivated trivalent influenza vaccine (IIV3-HD; Fluzone® High-Dose, Sanofi Pasteur) is available for adults ≥65 years of age. This study examined the safety and immunogenicity of a quadrivalent high-dose split-virion inactivated influenza vaccine (IIV4-HD). This was a randomized, modified double-blind, active-controlled, multi-center trial in healthy adults ≥65 years of age. Subjects were randomized in a 4:1:1 ratio to receive a single intramuscular injection of IIV4-HD, the licensed IIV3-HD, or an IIV3-HD containing the alternate B-lineage strain. Hemagglutination inhibition (HAI), seroneutralisation, and anti-neuraminidase antibody titers were measured at baseline and day 28. Solicited reactions were collected for up to 7 days, unsolicited adverse events up to 28 days, and serious adverse events up to 180 days. The primary immunogenicity objective was to demonstrate that IIV4-HD induces HAI geometric mean titers (GMTs) and seroconversion rates that are non-inferior to those induced by IIV3-HD. Secondary objectives were to describe the safety of IIV4-HD and IIV3-HD and to demonstrate that IIV4-HD induces HAI GMTs and seroconversion rates that are superior to those induced by IIV3-HD not containing the same B-lineage strain. The study included 2670 adults ≥65 years of age. For all four strains, HAI GMTs and seroconversion rates induced by IIV4-HD were non-inferior to those induced by IIV3-HDs containing the same strains. For both B strains, HAI GMTs and seroconversion rates induced by IIV4-HD were superior to those induced by IIV3-HD not containing the same B–lineage strain. Seroneutralisation and anti-neuraminidase antibody responses, measured in a subset of subjects, were similar. No new safety concerns were identified, and the safety profiles of IIV4-HD and IIV3-HD were similar. Adding a second B strain in IIV4-HD resulted in improved immunogenicity against the added strain without compromising the immunogenicity of the other strains or the vaccine’s tolerability. Clinical trial registration: NCT03282240.