Superior immunogenicity of high-dose quadrivalent inactivated influenza vaccine versus Standard-Dose vaccine in Japanese Adults ≥ 60 years of age: Results from a phase III,randomized clinical trial

BackgroundA high-dose, split-virion inactivated quadrivalent influenza vaccine (IIV4-HD; Sanofi) is being used for the prevention of influenza in multiple countries. This study examined the immunogenicity and safety of the IIV4-HD vaccine administered intramuscularly (IM) compared with a locally licensed standard-dose influenza vaccine (IIV4-SD) administered subcutaneously (SC) in Japan.MethodsThis was a phase III, randomized, modified double-blind, active-controlled, multi-center study in older adults ≥ 60 years of age conducted during the Northern Hemisphere (NH) influenza season of 2020–21 in Japan. Participants were randomized in a 1:1 ratio to receive a single IM injection of IIV4-HD or SC injection of IIV4-SD. Hemagglutination inhibition antibody and seroconversion rates were measured at baseline and day 28. Solicited reactions were collected for up to 7 days after vaccination, unsolicited adverse events up to 28 days after vaccination, and serious adverse events throughout the study.ResultsThe study included 2100 adults ≥ 60 years of age. IIV4-HD given IM induced superior immune responses versus IIV4-SD given SC as assessed by geometric mean titers for all four influenza strains. Superior seroconversion rates were also observed for IIV4-HD compared to IIV4-SD for all influenza strains. The safety profiles of IIV4-HD and IIV4-SD were similar. IIV4-HD was well tolerated in participants, with no safety concerns identified.ConclusionsIIV4-HD provided superior immunogenicity versus IIV4-SD and was well tolerated in participants ≥ 60 years of age in Japan. With superior immunogenicity based on the multiple randomized controlled trials and real-world evidence of trivalent high-dose formulation, IIV4-HD is expected to be the first differentiated influenza vaccine in Japan that offer a greater protection against influenza and its complications in adults 60 years of age and older.Study registrationNCT04498832 (clinicaltrials.gov); U1111-1225–1085 (who.int).     

Immune responses to intradermal and intramuscular inactivated influenza vaccine among older age group

BackgroudInfluenza viruses cause substantial morbidity, especially in older age groups. Thus, they are amongst high priority groups for routine vaccination. However, vaccine-induced immune responses and effectiveness were reported as relatively low. This study aims to systemically compare the immune responses elicited by intramuscular (IM) and intradermal (ID) injections with inactivated seasonal influenza vaccine among the older age group.MethodsA prospective, open-label, randomized study with a total of 221 adults (>60 years) were enrolled and randomized into 2 groups. Group I (n = 111) received an IM inactivated seasonal influenza vaccine while Group II (n = 110) received the same vaccine ID. Demographics and co-morbidity were collected at baseline. Safety data was collected 3 days post-vaccination using diary card. HAI, NAb and NAI titers were assessed prior to vaccination and at 30, 45, and 60 days post-vaccination. Data was analyzed using SPSS 11.5.ResultsBoth groups had similar BMI and co-morbidity. For ID and IM groups, significant differences were observed for seroconversion rate measured using HAI against H1N1 and H3N2 (58/111 vs 44/110 and 68/111 vs 54/110, respectively) being higher for those aged 60–65 years. However, no differences in HI antibody against B/Phuket were seen. For ID route, history of hyperlipidemia and hypertension were factors associated with high seroconversion rate towards influenza A (p = .001). The seroconversion rate risk ratio were 1.31 and 1.25 (p < .05) against A/California/07/09(H1N1) and A/Songkha/308/13 (H3N2), respectively. Interestingly, the GMT (95% CI) of baseline NAI antibodies among both groups were high (56.57 and 54.01 in the ID and IM groups, respectively). A 4-fold increase measured by NAI against A/California/07/09 (H1N1) were detected in 16.67% and 20% of participants who received ID or IM vaccination, respectively.ConclusionsThe seroconversion rates of HAI, NAb and NAI were modest, especially in those >65 years of age. However, it was higher in the ID group as compared to the IM group.Clinical trial registration: NCT02101749     

Needle-free delivery of influenza vaccine using the Med-Jet® H4 is efficient and elicits the same humoral and cellular responses as standard IM injection: A randomized trial

Background

Needle-free vaccine delivery systems have many potential advantages including increased vaccine compliance and decreased risk of needlestick injuries and syringe reuse. The Med-Jet® H4 is a gas-powered, auto-disabling disposable syringe jet injector. The Med-Jet family of products are currently being used in dermatology, podiatry, pain management and veterinary practices. The objectives of this study were to assess patient attitudes, time-efficiency, safety and immunogenicity of the seasonal influenza vaccine delivered by Med-Jet compared to the traditional needle-and-syringe.

Fc functional antibody responses to adjuvanted versus unadjuvanted seasonal influenza vaccination in community-dwelling older adults

BackgroundSeasonal influenza vaccination with a standard trivalent influenza vaccine (TIV) induces a modest, and cross-reactive, Fc functional antibody response in older adults. Recent improvements to influenza vaccines include a quadrivalent influenza vaccine (QIV) and a TIV adjuvanted with the squalene-based oil-in-water emulsion MF59.MethodsPre- and post-vaccination serum samples from older adults vaccinated with QIV (n = 27) and adjuvanted TIV (n = 44) were studied using hemagglutination inhibition (HAI) assays and dimeric Fc-gamma receptor IIIa binding ELISAs, as a surrogate of antibody-dependent cellular cytotoxicity (ADCC).ResultsWe found that the unadjuvanted QIV elicited a stronger HAI response against the H1N1 vaccine virus than the adjuvanted TIV. Post-vaccination levels of HA-specific ADCC antibodies were similar for older adults vaccinated with QIV and adjuvanted TIV. The ADCC response to influenza vaccination was largely determined by pre-vaccination or baseline levels of these antibodies, with older adults with low baseline levels of ADCC activity demonstrating greater post-vaccination rises.ConclusionsIn this cohort of community-dwelling older adults, the QIV was at least as good as the adjuvanted TIV in the induction of ADCC and HAI responses. Further studies on how these antibody responses translate to efficacy in preventing influenza infections are warranted.     

Evaluation of conserved and variable influenza antigens for immunization against different isolates of H5N1 viruses

The combination of rapid evolution and high mortality in human cases of infections has raised concerns that the H5N1 avian influenza virus may become a new, possibly severe, pandemic virus. Vaccination is likely to be the most efficient strategy to mitigate the impact of the next influenza pandemic. The present study evaluates B and T cell immune responses generated by the H5N1 viral antigens, hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), or the M2 ion channel in parallel, expressed from a DNA vaccine vehicle. Protection studies of immunized mice challenged with 100 LD50 of homologous or heterologous H5N1 viruses indicate that HA afforded better protection than the NA, NP or M2 DNA vaccines. The antibody response was also higher in HA-vaccinated mice as determined by hemagglutination inhibition (HI) and neutralizing antibodies (NAB) assays. Interestingly, the T cell response was higher against HA than against NA, NP or M2 and was detectable at low doses of the DNA–HA vaccine capable of inducing complete protection, despite the absence of a detectable B cell response. This study emphasizes the need to evaluate the relationship between both arms of the adaptive immune responses in regards to protective efficacy against influenza virus.     

Evaluation of the cellular immune responses induced by a non-adjuvanted inactivated whole virus A/H5N1/VN/1203 pandemic influenza vaccine in humans

In the present study the homologous and heterologous type and subtype specific cellular immune response induced by a wild type inactivated whole virus H5N1 Influenza (A/Vietnam/1203/2004) vaccine was evaluated. Two immunizations with the Vero cell derived H5N1 influenza vaccine on Day 0 and Day 21 induced significant H5N1 vaccine specific and H5 haemagglutinin specific clade and cross-clade reactive CD4⁺ T cell responses, which were maintained at significant levels for at least 6 months. The H5N1 vaccine specific response cross-reacted with the H1N1, but not with H3N2 or B seasonal Influenza strains. The vaccine significantly increased the number of H5N1 specific and H5 haemagglutinin specific memory B cells, 6 months after the primary immunization, however no H1N1 specific cross-reactivity was observed. Importantly, the inactivated whole virus H5N1 vaccine was just as effective in inducing CD4⁺ T cell and memory B cell response in the elderly (60 years or over) as in the adult population (18-59 years).     

Co-administration of certain DNA vaccine combinations expressing different H5N1 influenza virus antigens can be beneficial or detrimental to immune protection

Achieving broad-spectrum immunity against emerging zoonotic viruses such as avian influenza H5N1 and other possible pandemic viruses will require generation of cross-protective immune responses. Strong antibody responses generated against the H5HA protein are protective, however, antigenic variation between diverging isolates can interfere with virus neutralization. The current study investigates co-administration of an H5 HA DNA vaccine with other variable and conserved influenza antigens (NA, NP, and M2). All antigens were derived from the A/Hanoi/30408/2005 (H5N1) virus and the contribution towards overall protection and immune activation was assessed against lethal homologous and heterologous challenges. An (HA + NA) combination afforded the best protection against homologous challenge and (HA + NP) was comparable to HA alone against heterologous A/Hong Kong/483/1997 challenge. Interestingly, combining all four H5 antigens at a single site did not improve protection against matched challenge and unexpectedly reduced survival by 30% against a heterologous challenge. Survival was also significantly decreased against heterologous challenge following combination of (HA + NP) with an unrelated antigen. Although there were no significant changes in antibody titres, significantly lower T-cell responses were detected against all antigens except HA in each combination. Co-administration of the vaccines at different injection sites restored T-cell responses but did not improve overall protection. Similar observations were also recorded following combination of HA and NP antigens using two different adenovirus-based backbones. Overall, the data suggest that co-administering certain H5N1 antigens offer better or comparable protection to HA alone, however, combining extra antigens may be unnecessary and lead to unfavourable immune responses.     

Intranasal administration of a flagellin-adjuvanted inactivated influenza vaccine enhances mucosal immune responses to protect mice against lethal infection

The influenza virus, a mucosal pathogen that infects the respiratory tract, is a major global health issue. There have been attempts to mucosally administer inactivated influenza vaccines to induce both mucosal and systemic immune responses. However, mucosally administered inactivated influenza vaccine has low immunogenicity, which is partially due to the lack of an effective mucosal adjuvant. The development of a safe and effective mucosal adjuvant is a prerequisite to the practical use of a mucosal inactivated influenza vaccine. We have previously demonstrated that a bacterial flagellin, Vibrio vulnificus FlaB, when mixed with antigen and administered intranasally, exerts a strong mucosal adjuvant activity by stimulating the Toll-like receptor 5 (TLR5). In this study, we tested whether the FlaB protein could serve as an effective mucosal adjuvant for an inactivated trivalent influenza vaccine (TIV) manufactured for humans; in a murine vaccination model, this vaccine consists of A/Brisbane/59/07 (H1N1 subtype), A/Uruguay/716/07 (H3N2 subtype), and B/Florida/4/06 (B type). Intranasal co-administration of the TIV with FlaB induced prominent humoral responses as demonstrated by high influenza-specific IgA levels in both the mucosal secretions and serum and significant specific IgG induction in the systemic compartment. The FlaB protein significantly potentiated influenza-specific cytokine production by draining lymph node cells and splenocytes. The FlaB mucosal adjuvant conferred excellent protection against a lethal challenge with a live virulent virus with high hemagglutination inhibition (HAI) antibody (Ab) titers. The FlaB did not accumulate in the olfactory nerve and epithelium, guaranteeing against a retrograde uptake into the central nervous system. These results suggest that FlaB can be used as a promising mucosal adjuvant for nasal inactivated influenza vaccine development.     

A predictive model of the economic effects of an influenza vaccine adjuvant for the older adult (age 65 and over) population

Immunosenescence decreases influenza vaccine efficacy in older adults (age 65 and over). Strategies such as vaccine adjuvants are being developed to overcome immunosenescence. Our computer simulation model represented the decision to give an older adult either standard influenza vaccine or adjuvanted influenza vaccine and found the adjuvanted vaccine to be dominant in many scenarios, resulting in lowered cost and greater effectiveness. An adjuvanted vaccine that is 100% effective in overcoming immunosenescence remained dominant until its cost exceeded the standard vaccine cost by $65. In a single influenza season, the adjuvant would prevent 496,533 influenza cases, 171,981 hospitalizations, and 70,429 deaths.     

Safety and immune responses following administration of H1N1 live attenuated influenza vaccine in Thais

Background

Emergence and rapid spread of influenza H1N1 virus prompted health authorities to develop a safe and effective influenza vaccine for domestic use. The Thai Government Pharmaceutical Organization (GPO) with technical support from Russia through WHO had prepared a pandemic live attenuated vaccine (PLAIV) using ca-ts attenuated candidate strain A/17/CA/2009/38 (H1N1) for Thais.

Methods

Each participant received two doses of intranasal H1N1 vaccine or placebo 21 days apart. All were followed up at 7, 21, 42 and 60 days after first immunization. Blood was drawn for hemagglutination inhibition (HAI) assay from all participants at days 1, 21, 42, and 60 after first immunization. A subset of 40 participants aged 19–49 years was randomly selected for nasal washing at days 1, 21, 42, and 60 to assess IgA using direct enzyme-linked immunosorbent assay (ELISA) along with serum HAI and microneutralization (MN) assay determination.

Results

A total of 363 subjects aged 12–75 years were randomized into 2 groups (271 vaccinees:92 placebos). Almost all AEs were mild to moderate. Local reactions were stuffy nose (22.3%), runny nose (25.1%), scratchy throat (27.2%) and sore throat (19.3%). Systemic reactions included headache (21.7%), myalgia (13.8%), fatigue (16.8%) and postnasal drip (19.9%). On day 60, HAI seroconversion rates for vaccine:placebo group were 30.3:6.0 for ITT and 29.4:5.1 for PP analysis. Children showed highest seroconversion rate at 44, but it decreased to 39.4 when all 3 assays (HAI, MN assay and ELISA) from subgroup analysis were considered.

Conclusion

The vaccine candidate is safe. The use of more than one assay may be needed for evaluation of immune response because live attenuated vaccines could effectively induce different kinds of responses. Different individuals could also mount different kinds of immune response, even to the same antigen.     

A postmarketing evaluation of the frequency of use and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years

The 2007 US approval for use of live attenuated influenza vaccine (LAIV) in children aged 24-59 months included precautions against use in (1) children <24 months and children aged 24-59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. A postmarketing commitment was initiated to monitor LAIV use and the frequency of select safety outcomes in these cohorts. Vaccination rates and the frequency of hospitalizations or emergency department visits within 42 days after LAIV and trivalent inactivated influenza vaccine (TIV) administration were estimated from 2007 to 2009 claims data from a health insurance database. Rates of LAIV use per 10,000 child-days among cohorts 1, 2, and 4 were low relative to rates among the LAIV-recommended population (2007-2008; 0.03-0.78 vs. 1.32, 2008-2009; 0.08-3.26 vs. 5.94). However, rates of LAIV use per 10,000 child-days in cohort 3 were similar to rates among the LAIV-recommended population (2007-2008; 1.55 vs. 1.32, 2008-2009; 5.01 vs. 5.94). The rate of emergency department visits/hospitalizations within 42 days of vaccination with LAIV was the same as or less than the rate within 42 days of vaccination with TIV. Less restricted LAIV use in children with past wheezing may be related to the broad definition of recurrent wheezing used in national guidelines and the current study. In the small number of nonrecommended children receiving LAIV, no safety signals were identified.     

Cell mediated immune responses following revaccination with an influenza A/H5N1 vaccine

PurposeThe study aims were to determine whether inactivated influenza A/H5N1 vaccine administration elicited cell mediated immune (CMI) responses and the impact of adjuvant, vaccine dose and subject age on these responses.MethodsAdults who were previously primed with either adjuvanted or unadjuvanted, inactivated, A/H5N1/Vietnam/1203/2004 (Clade 1) vaccine or unprimed (received placebo) in previous vaccine studies were randomized to receive one (primed) or two (unprimed) 15- or 90-mcg doses of inactivated, A/H5N1/Indonesia/05/05 (Clade 2) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from a subset of vaccinees to assess CMI responses using IFN-γ and granzyme B ELISPOT assays. Cytokine measurements were performed on PBMC supernatants after stimulation with H5N1 virus.ResultsPBMCs were available from 177 participants; 88 and 89 received 15-mcg and 90-mcg of unadjuvanted clade 2 vaccine, respectively. Following H5N1 clade 1 stimulation, IFN-γ but not granzyme B normalized spot-forming cell numbers had statistically significant increased numbers at each of the post-vaccination timepoints compared to baseline in pooled analyses of all vaccine doses and age groups. Clade 2 stimulation resulted in statistically significant increased numbers of IFN-γ cells only 180 days following the last vaccination. Responses were similar among younger and older study participants, as were responses among those primed with alum-adjuvanted or non-adjuvanted clade 1 H5N1 vaccines. The dosage of clade 2 vaccine did not impact CMI responses among primed subjects, but responses were statistically significantly greater in unprimed recipients of the 90-mcg dosage compared to unprimed recipients of the 15-mcg dosage. IFN-γ levels in the supernatants of stimulated PBMC were strongly correlated with IFN-γ ELISPOT results.ConclusionCMI responses occur in adults administered influenza A/H5N1 inactivated influenza vaccine.     

Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses during infection of human nasal epithelial cell cultures

Influenza viruses are global pathogens that infect approximately 10–20% of the world's population each year. Vaccines, including the live attenuated influenza vaccine (LAIV), are the best defense against influenza infections. The LAIV is a novel vaccine that actively replicates in the human nasal epithelium and elicits both mucosal and systemic protective immune responses. The differences in replication and innate immune responses following infection of human nasal epithelium with influenza seasonal wild type (WT) and LAIV viruses remain unknown. Using a model of primary differentiated human nasal epithelial cell (hNECs) cultures, we compared influenza WT and antigenically-matched cold adapted (CA) LAIV virus replication and the subsequent innate immune response including host cellular pattern recognition protein expression, host innate immune gene expression, secreted pro-inflammatory cytokine production, and intracellular viral RNA levels. Growth curves comparing virus replication between WT and LAIV strains revealed significantly less infectious virus production during LAIV compared with WT infection. Despite this disparity in infectious virus production the LAIV strains elicited a more robust innate immune response with increased expression of RIG-I, TLR-3, IFNβ, STAT-1, IRF-7, MxA, and IP-10. There were no differences in cytotoxicity between hNEC cultures infected with WT and LAIV strains as measured by basolateral levels of LDH. Elevated levels of intracellular viral RNA during LAIV as compared with WT virus infection of hNEC cultures at 33 °C may explain the augmented innate immune response via the up-regulation of pattern recognition receptors and down-stream type I IFN expression. Taken together our results suggest that the decreased replication of LAIV strains in human nasal epithelial cells is associated with a robust innate immune response that differs from infection with seasonal influenza viruses, limits LAIV shedding and plays a role in the silent clinical phenotype seen in human LAIV inoculation.     

Kinetics of viral shedding and immune responses in adults following administration of cold-adapted influenza vaccine

The optimal type and timing of specimens to study the immune responses to cold-adapted influenza vaccine (CAIV) and shedding of vaccine virus are not well established. Healthy adults were vaccinated with CAIV (n = 10) or trivalent influenza vaccine (TIV) (n = 5). Shedding of vaccine strain influenza B was detected by culture in 6 of 10 CAIV recipients; influenza A was also detected in one of these subjects. Viral shedding by quantitative RT-PCR was detected in 9 of 10 subjects. We detected a ≥2-fold increase in influenza-specific IgA in nasal wash in 80–100% of CAIV recipients following vaccination, but specific IgG increased in neither nasal wash nor saliva. Recipients of TIV had significant increases in specific serum IgG antibodies. Recipients of both CAIV and TIV had significant increases in IFNγ-secreting peripheral blood mononuclear cells (PBMCs). PBMCs from subjects receiving CAIV showed a higher proportion of functional, tissue-tropic T-cells (CD4+CD69+CD18+MIP1α+) specific for homotypic and heterosubtypic strains of influenza by flow cytometry.     

Estimating influenza vaccine effectiveness: Evolution of methods to better understand effects of confounding in older adults

Older adults are at high risk for serious complications of influenza illness and loss of vaccine-mediated protection. It is increasingly recognized that in addition to age, multiple chronic conditions and associated frailty contribute to the decline in vaccine effectiveness in this population. However, observational studies have been fraught with issues of confounding related to the degree of frailty and functional decline, measures of which are not included in standard administrative health care databases that are used to calculate vaccine effectiveness. This issue has led to the identification of confounding by indication or from “healthy vaccinee” bias, which respectively lead to underestimates or overestimates of influenza vaccine effectiveness. In addition, the sensitivity and specificity of the criteria used to define influenza-like illness declines with increasing age due to atypical presentations of illness and the inability to distinguish between influenza and other respiratory viruses. The test-negative case:control design has emerged as a method to estimate influenza vaccine effectiveness by comparing vaccination rates in those with laboratory-confirmed influenza to those with other acute viral respiratory illnesses. This review provides a perspective on how test-negative case:control study designs and new insights into mechanisms of protection have considerably strengthened influenza vaccination policy decisions for older adults that have historically been undermined by the conclusions of observational studies.     

Randomized trial comparing the safety and antibody responses to live attenuated versus inactivated influenza vaccine when administered to breastfeeding women

BackgroundLive attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are both licensed for administration to nursing mothers. Little is known about the potential for transmission of LAIV viruses from the mother to the infant and the comparative breast milk antibody responses to LAIV and IIV.MethodsWe performed a randomized, double-blind study comparing the immunogenicity of LAIV to IIV when administered to nursing mothers. The safety of LAIV to IIV in women and their infants was also compared. Women received LAIV + intramuscular placebo, or IIV + intranasal placebo on Day 0. Breast milk and nasal swabs (from women and infants) were collected on Days 0, 2, and 8 for detection of LAIV. Breast milk and serum antibody responses were measured at Days 0 and 28. The primary hypothesis was that LAIV would provide superior induction of breast milk IgA responses to influenza as compared to IIV when administered to nursing mothers.ResultsBreast milk IgG, breast milk IgA (H1N1 only), serum hemagglutination inhibition (HAI), and serum IgG responses were significantly higher following administration of IIV compared to LAIV. Receipt of either LAIV or IIV was safe in women and their infants. One (1%) LAIV recipient transmitted vaccine virus to her infant who remained well. No influenza virus was detected in breast milk.ConclusionsBreast milk and serum antibody responses were higher for IIV compared to LAIV. LAIV and IIV were safe for nursing women but there was one (1%) possible transmission of LAIV to an infant. This study suggests that IIV may be the preferred vaccine for nursing mothers.     

Effectiveness of trivalent inactivated influenza vaccine among community-dwelling older adults in Thailand: A two-year prospective cohort study

Background

We conducted a two-year prospective cohort study to measure the effectiveness of trivalent inactivated influenza vaccine (IIV3) to prevent laboratory-confirmed influenza among community-dwelling Thai adults aged ≥65?years during 2015–16 and 2016–17 influenza seasons.

Activation of cross-reactive mucosal T and B cell responses in human nasopharynx-associated lymphoid tissue in vitro by Modified Vaccinia Ankara-vectored influenza vaccines

Recent efforts have been focused on the development of vaccines that could induce broad immunity against influenza virus, either through T cell responses to conserved internal antigens or B cell response to cross-reactive haemagglutinin (HA). We studied the capacity of Modified Vaccinia Ankara (MVA)-vectored influenza vaccines to induce cross-reactive immunity to influenza virus in human nasopharynx-associated lymphoid tissue (NALT) in vitro. Adenotonsillar cells were isolated and stimulated with MVA vaccines expressing either conserved nucleoprotein (NP) and matrix protein 1 (M1) (MVA-NP-M1) or pandemic H1N1 HA (MVA-pdmH1HA). The MVA vaccine uptake and expression, and T and B cell responses were analyzed. MVA-vectored vaccines were highly efficient infecting NALT and vaccine antigens were highly expressed by B cells. MVA-NP-M1 elicited T cell response with greater numbers of IFNγ-producing CD4+ T cells and tissue-resident memory T cells than controls. MVA-pdmH1HA induced cross-reactive anti-HA antibodies to a number of influenza subtypes, in an age-dependent manner. The cross-reactive antibodies include anti-avian H5N1 and mainly target HA2 domain. Conclusion: MVA vaccines are efficient in infecting NALT and the vaccine antigen is highly expressed by B cells. MVA vaccines expressing conserved influenza antigens induce cross-reactive T and B cell responses in human NALT in vitro, suggesting the potential as mucosal vaccines for broader immunity against influenza.     

Live attenuated influenza vaccine (LAIV) impacts innate and adaptive immune responses

Influenza A infection induces a massive inflammatory response in the lungs that leads to significant illness and increases the susceptibility to secondary bacterial pneumonia. The most efficient way to prevent influenza infection is through vaccination. While inactivated vaccines induce protective levels of serum antibodies to influenza hemaglutinin (HA) and neuraminidase (NA) surface proteins, these are strain specific and offer little protection against heterosubtypic influenza viruses. In contrast, live attenuated influenza vaccines (LAIVs) induce a T cell response in addition to antibody responses against HA and NA surface proteins. Importantly, LAIV vaccination induces a response in a mouse model that protects against illness due to heterosubtypic influenza strains. While it is not completely clear what is the mechanism of action of LAIV heterosubtypic protection in humans, it has been shown that LAIV induces heterosubtypic protection in mice that is dependent upon a Type 1 immune response and requires CD8 T cells. In this study, we show that LAIV-induced immunity leads to significantly reduced viral titers and inflammatory responses in the lungs of mice following heterosubtypic infection. Not only are viral titers reduced in LAIV vaccinated mice, the amounts of inflammatory cytokines and chemokines in lung tissue are significantly lower. Additionally, we show that LAIV vaccination of healthy adults also induces a robust Type 1 memory response including the production of chemokines and cytokines involved in T cell activation and recruitment. Thus, our results indicate that LAIV vaccination functions by inducing immune memory which can act to modulate the immune response to subsequent heterosubtypic challenge by influencing both innate and adaptive responses.