Effects of Different Adjuvants in the Context of Intramuscular and Intranasal Routes on Humoral and Cellular Immune Responses Induced by Detergent-Split A/H3N2 Influenza Vaccines in Mice

ABSTRACTInfluenza A/H3N2 viruses have caused the most severe epidemics since 1968 despite current immunization programs with inactivated vaccines. We undertook a side-by-side preclinical evaluation of different adjuvants (Alum, AS03, and Protollin) and routes of administration (intramuscular [i.m.] and intranasal [i.n.]) for assessing their effect on the immunogenicity and cross-reactivity of inactivated split vaccines (A/H3N2/New York/55/2004). Humoral and T cell-mediated immune responses against the homologous virus and a heterologous drifted strain (A/H3N2/Wisconsin/67/2005) were measured in BALB/c mice at 2, 6, and 19 weeks postboost. The AS03- and Alum-adjuvanted i.m. vaccines induced at least an 8-fold increase over the nonadjuvanted vaccine in functional antibody titers against both the homotypic and heterotypic strains and low IgG2a and high IgG1 levels, suggesting a mixed Th1/Th2 response with a Th2 trend. The Protollin-adjuvanted i.n. vaccine induced the lowest IgG1/IgG2a ratio, which is indicative of a mixed Th1/Th2-type profile with a Th1 trend. This adjuvanted vaccine was the only vaccine to stimulate a mucosal IgA response. Whatever the timing after the boost, both hemagglutination inhibition (HAI) and microneutralization (MN) titers were higher with the AS03-adjuvanted i.m. vaccine than with the protollin-adjuvanted i.n. vaccine. Finally, the Alum-adjuvanted i.m. vaccine and the lower-dose Protollin-adjuvanted i.n. vaccine elicited significantly higher CD4+Th1 and Th2 responses and more gamma interferon (IFN-γ)-producing CD8+T cells than the nonadjuvanted vaccine. Our data indicate that the adjuvanted vaccines tested in this study can elicit stronger, more persistent, and broader immune responses against A/H3N2 strains than nonadjuvanted inactivated influenza vaccines.

Download Full-text

Intersection of Sex and Frailty in Humoral Immune Responses to Influenza Vaccine in Community-Dwelling Older Adults

Innovation in Aging ◽

10.1093/geroni/igaa057.869 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 271-272

Author(s):

Janna Shapiro ◽

Helen Kuo ◽

Rosemary Morgan ◽

Huifen Li ◽

Sabra Klein ◽

...

Keyword(s):

Older Adults ◽

Immune Responses ◽

Influenza A ◽

Community Dwelling ◽

Influenza Vaccines ◽

Health Study ◽

Cardiovascular Health Study ◽

High Dose ◽

Humoral Immune ◽

Humoral Immune Responses

Abstract Older adults bear the highest burden of severe disease and complications associated with seasonal influenza, with annual vaccination serving as the best option for protection. Variability in vaccine efficacy exists, yet the host factors that affect immune responses to inactivated influenza vaccines (IIV) are incompletely understood. We hypothesized that sex and frailty interact to affect vaccine-induced humoral responses among older adults. To test this hypothesis, community-dwelling adults above 75 years of age were recruited yearly, assessed for frailty (as defined by the Cardiovascular Health Study criteria), and vaccinated with the high-dose trivalent IIV. Humoral immune responses were evaluated via hemagglutination inhibition titers. The study began during the 2014-2015 influenza season, with yearly cohorts ranging from 76-163 individuals. A total of 617 vaccinations were delivered from 2014-2019. In preliminary analyses, the outcome of interest was seroconversion, defined as ≥ 4-fold rise in titers. Crude odds ratios suggest that females are more likely to seroconvert to influenza A strains (H1N1: OR = 1.39, (0.98-1.96) ; H3N2: 1.17 (0.85 – 1.62)), while males are more likely to seroconvert to the B strain (OR = 0.85 (0.60 – 1.22)). Furthermore, this sex difference was modified by frailty – for example, the odds of seroconversion to H1N1 were 65% higher for females than males among those who were nonfrail, and only 30% higher among females who were frail. Together, these results suggest that sex and frailty interact to impact immune responses to influenza vaccines. These findings may be leveraged to better protect vulnerable populations.

Download Full-text

Adjuvanted recombinant hemagglutinin H7 vaccine to highly pathogenic influenza A(H7N9) elicits high and sustained antibody responses in healthy adults

npj Vaccines ◽

10.1038/s41541-021-00287-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Christine M. Oshansky ◽

◽

James King ◽

Di Lu ◽

James Zhou ◽

...

Keyword(s):

Influenza A ◽

Study Groups ◽

Cross Reactivity ◽

Healthy Adults ◽

Response Strategy ◽

Seroprotection Rate ◽

Highly Pathogenic ◽

Homologous Virus ◽

Human Infections ◽

Epidemic Wave

AbstractAn unprecedented number of human infections with avian influenza A(H7N9) in the fifth epidemic wave during the winter of 2016–2017 in China and their antigenic divergence from the viruses that emerged in 2013 prompted development of updated vaccines for pandemic preparedness. We report on the findings of a clinical study in healthy adults designed to evaluate the safety and immunogenicity of three dose levels of recombinant influenza vaccine derived from highly pathogenic A/Guangdong/17SF003/2016 (H7N9) virus adjuvanted with AS03 or MF59 oil-in water emulsions. Most of the six study groups meet the FDA CBER-specified vaccine licensure criterion of 70% seroprotection rate (SPR) for hemagglutination inhibition antibodies to the homologous virus. A substantial proportion of subjects show high cross-reactivity to antigenically distinct heterologous A(H7N9) viruses from the first epidemic wave of 2013. These results provide critical information to develop a pandemic response strategy and support regulatory requirements for vaccination under Emergency Use Authorization.

Download Full-text

From influenza infection to anti-ADAMTS13 autoantibodies via cross-reactivity

Infection International ◽

10.2478/ii-2019-0002 ◽

2018 ◽

Vol 7 (4) ◽

pp. 113-120

Author(s):

Darja Kanduc

Keyword(s):

Immune Responses ◽

Thrombotic Thrombocytopenic Purpura ◽

Von Willebrand Factor ◽

Influenza A ◽

Influenza Infection ◽

Cross Reactivity ◽

Influenza Viruses ◽

Thrombocytopenic Purpura ◽

Von Willebrand ◽

Willebrand Factor

Abstract Autoantibodies (AAbs) against von Willebrand factor (vWF)-cleaving protease ADAMTS13 causally relate to thrombotic thrombocytopenic purpura (TTP). How anti-ADAMTS13 AAbs are generated is unknown. Starting from reports according to which influenza infection can trigger TTP by the production of ADAMTS13 AAbs, this study explores influenza viruses and ADAMTS13 protein for common peptide sequences that might underlie anti-influenza immune responses able to cross-react with ADAMTS13. Results document that numerous peptides are shared between influenza A and B viruses and ADAMTS13, thus supporting the hypothesis of cross-reactivity as a mechanism driving the generation of anti-ADAMTS13 AAbs.

Download Full-text

Immunity to attenuated influenza virus WRL 105 infection induced by heterologous, inactivated influenza A virus vaccines

Journal of Hygiene ◽

10.1017/s0022172400053158 ◽

1977 ◽

Vol 79 (3) ◽

pp. 321-332 ◽

Cited By ~ 47

Author(s):

C. W. Potter ◽

R. Jennings ◽

K. Nicholson ◽

D. A. J. Tyrrell ◽

K. G. Dickinson

Keyword(s):

Influenza Virus ◽

Hong Kong ◽

Influenza A ◽

Serum Antibody ◽

Fold Increase ◽

Vaccine Virus ◽

Cross Reactivity ◽

Variable Response ◽

Challenge Virus ◽

Two Factors

SUMMARYGroups of student volunteers were immunized with one of five different inactivated influenza virus vaccines. The concentration of virus in the various vaccines differed by both the international unitage test and by the concentration of haemagglutinin, as measured by the single radial diffusion test; the results of the two methods of standardization showed no correlation. The serum HI response to immunization was variable; volunteers given A/England/72 showed a 16·6-fold increase in homologous serum antibody titre whilst volunteers given A/Hong Kong/68 vaccine showed a 4·2-fold increase. The variable response of volunteers to immunization could not be explained by the varied concentration of virus in the vaccines, as measured by either test, the titres of serum HI antibody present before immunization, or a combination of these two factors.The ability to infect volunteers with WRL 105 virus 4 weeks after immunization with heterologous, inactivated virus vaccine was directly related to the degree of cross-reactivity between the haemagglutinins of this vaccine virus and WRL 105 virus. Thus, the greatest number of infections by the challenge virus were seen in volunteers given A/Hong Kong/68 vaccine, less were observed in volunteers given A/England/72 vaccine, and least were found in groups given A/Port Chalmers/73 or A/Scotland/74 vaccine. However, compared with the incidence of infection in volunteers given B/Hong Kong/73 vaccine, all the heterologous influenza A vaccine gave some immunity to challenge infection.

Download Full-text

Heterosubtypic cross-reactivity of HA1 antibodies to influenza A, with emphasis on nonhuman subtypes (H5N1, H7N7, H9N2)

10.1101/116327 ◽

2017 ◽

Author(s):

Dennis E. te Beest ◽

Erwin de Bruin ◽

Sandra Imholz ◽

Marion Koopmans ◽

Michiel van Boven

Keyword(s):

Immune Responses ◽

Influenza A ◽

Protein Microarray ◽

Age Distribution ◽

Cross Reactivity ◽

Influenza A Viruses ◽

Cross Sectional ◽

Before And After ◽

2009 H1n1 ◽

Protein Microarray Analysis

AbstractEpidemics of influenza A vary greatly in size and age distribution of cases, and this variation i attributed to varying levels of pre-existing immunity. Recent studies have shown that antibody mediated immune responses are more cross-reactive than previously believed, and shape patterns of humoral immunity to influenza A viruses over long periods. Here we quantify antibody responses to the hemagglutinin subunit 1 (HA1) across a range of subtypes using protein microarray analysis of cross-sectional serological surveys carried out in the Netherlanc before and after the A/2009 (H1N1) pandemic. We find significant associations of responses, both within and between subtypes. Interestingly, substantial overall reactivity is observed to HA1 of avian H7N7 and H9N2 viruses. Seroprevalence of H7N7 correlates with antibody titer to A/1968 (H3N2), and is highest in persons born between 1954 and 1969. Seroprevalence of H9N2 is high across all ages, and correlates strongly with A/1957 (H2N2). This correlation is most pronounced in A/2009 (H1N1) infected persons born after 1968 who have never encountered A/1957 (H2N2)-like viruses. We conclude that heterosubtypic antibody crossreactivity, both between human subtypes and between human and nonhuman subtypes, is common in the human population.

Download Full-text

Immune Cross-Opsonization Withinemm Clusters Following Group AStreptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity

Clinical Infectious Diseases ◽

10.1093/cid/cix599 ◽

2017 ◽

Vol 65 (9) ◽

pp. 1523-1531 ◽

Cited By ~ 23

Author(s):

Hannah R Frost ◽

Delphine Laho ◽

Martina L Sanderson-Smith ◽

Paul Licciardi ◽

Susan Donath ◽

...

Keyword(s):

Immune Responses ◽

Antibody Titer ◽

Skin Infection ◽

Vaccine Development ◽

Fold Increase ◽

Cross Reactivity ◽

Enzyme Linked Immunosorbent Assay ◽

Serological Response ◽

Protective Antibodies ◽

The Mean

Abstract Background Group AStreptococcus (GAS) skin infections are particularly prevalent in developing nations. The GAS M protein, by which strains are differentiated into >220 differentemm types, is immunogenic and elicits protective antibodies. A major obstacle for vaccine development has been the traditional understanding that immunity following infection is restricted to a singleemm type. However, recent evidence has led to the hypothesis of immune cross-reactivity betweenemm types. Methods We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 majoremm clusters (E4, E6, and D4). Pre- and postinfection sera were assayed by enzyme-linked immunosorbent assay with N-terminal M peptides and bactericidal assays using the infecting-type strain,emm cluster–related strains, and nonrelated strains. Results Twenty of the 53 paired sera demonstrated a ≥4-fold increase in antibody titer against the infecting type. When tested against all cluster-related M peptides, we found that 9 of 17 (53%) paired sera had a ≥4-fold increase in antibody titer to cluster-related strains as well. When grouped by cluster, the mean change to cluster-relatedemm types in E4 and E6 was >4-fold (5.9-fold and 19.5-fold, respectively) but for D4 was 3.8-fold. The 17 paired sera were tested in bactericidal assays against selected cluster-related and nonrelated strains. While the responses were highly variable, numerous instances of cross-reactive killing were observed. Conclusions These data demonstrate that M type–specific and cross-reactive immune responses occur following skin infection. The cross-reactive immune responses frequently align withemm clusters, raising new opportunities to design multivalent vaccines with broad coverage.

Download Full-text

The strong positive correlation between effective affinity and infectivity neutralization of highly cross-reactive monoclonal antibody IIB4, which recognizes antigenic site B on influenza A virus haemagglutinin

Microbiology ◽

10.1099/0022-1317-81-7-1727 ◽

2000 ◽

Vol 81 (7) ◽

pp. 1727-1735 ◽

Cited By ~ 12

Author(s):

F. Kostolanský ◽

E. Varečková ◽

T. Betáková ◽

V. Mucha ◽

G. Russ ◽

...

Keyword(s):

Monoclonal Antibody ◽

Influenza A Virus ◽

Influenza A ◽

Antigenic Site ◽

Fold Increase ◽

Cross Reactivity ◽

Influenza Viruses ◽

Mass Action ◽

Strong Positive Correlation ◽

Positive Correlation

Monoclonal antibody (MAb) IIB4 displays a rare combination of virus neutralization (VN) activity and broad cross-reactivity with influenza A virus strains of the H3 subtype isolated in a period from 1973 to 1988. The epitope of this antibody has been identified as around HA1 residues 198, 199 and 201. Here we report that residues 155, 159, 188, 189 and 193 also influence the binding of this antibody. We have used this antibody to study the relationship between antibody affinity and VN activity. Using one MAb and a single epitope on the haemagglutinin (HA) of different influenza viruses we found a strong positive correlation between effective affinity and VN activity of MAb IIB4. A 10-fold increase in effective affinity corresponded to the 2000-fold increase in VN titre. It follows from the law of mass action that for an effective affinity K=9×108 l/mol, 50% VN was achieved at approx. 10% occupation of HA spikes with antibody. In contrast, for an effective affinity K=6×107 l/mol, to achieve 50% VN, occupation of up to 98% of HA spikes was required. An effective affinity about K=6×107 l/mol thus represents the limiting value for VN because a further decrease in the affinity cannot be compensated by a higher concentration of antibody.

Download Full-text

Cellular Immune Responses in Children and Adults Receiving Inactivated or Live Attenuated Influenza Vaccines

Journal of Virology ◽

10.1128/jvi.01460-06 ◽

2006 ◽

Vol 80 (23) ◽

pp. 11756-11766 ◽

Cited By ~ 231

Author(s):

Xiao-Song He ◽

Tyson H. Holmes ◽

Caiqiu Zhang ◽

Kutubuddin Mahmood ◽

George W. Kemble ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Influenza Vaccine ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Vaccines ◽

Cellular Immune Responses ◽

Ifn Γ ◽

The Mean ◽

Cellular Immune

ABSTRACT The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-γ) flow cytometry assay was used to measure IFN-γ-producing (IFN-γ+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-γ+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-γ+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-γ+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56dim NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.

Download Full-text

Development of a BNP1-32 Immunoassay That Does Not Cross-React with proBNP

Clinical Chemistry ◽

10.1373/clinchem.2016.269712 ◽

2017 ◽

Vol 63 (6) ◽

pp. 1110-1117 ◽

Cited By ~ 12

Author(s):

Lynley K Lewis ◽

Sara D Raudsepp ◽

Tim G Yandle ◽

Timothy C Prickett ◽

A Mark Richards

Keyword(s):

New York ◽

Cardiac Dysfunction ◽

Nyha Class ◽

Heart Association ◽

Fold Increase ◽

Cross Reactivity ◽

Healthy Controls ◽

Diagnosis And Prognosis ◽

New York Heart Association ◽

Abbott Architect

Abstract BACKGROUND Plasma B-type natriuretic peptide (BNP) concentration reflects cardiac dysfunction and assists in determining the diagnosis and prognosis of heart failure (HF). Current BNP assays overestimate circulating bioactive BNP1-32 concentrations as they also detect less active BNP metabolites and proBNP. A specific BNP1-32 assay with negligible cross-reactivity to proBNP and/or BNP metabolites may be advantageous. METHODS We developed a Luminex-based specific BNP1-32 immunoassay and compared results obtained from 3 other BNP assays (a Luminex-based total-BNP assay, our BNP RIA, and the commercially available Abbott Architect BNP assay) in plasma from 42 patients with HF and 22 healthy controls. RESULTS The BNP1-32 assay showed 57% cross-reactivity with BNP2-32, but ≤0.1% cross-reactivity to BNP3-32, other BNP metabolites, and proBNP; its detection limit was 0.35 ng/L; and intra- and interassay CVs were <15%. BNP immunoreactivity increased with HF severity (median concentrations being 0.3, 0.8, 26.2, and 17.3 ng/L in healthy controls and 40.7, 139, 465, and 1778 ng/L in HF patients for the BNP1-32, total-BNP, BNP RIA, and Abbott BNP assays respectively). The fold increase between HF cases with the New York Heart Association (NYHA) class IV was significantly greater with the BNP1-32 assay than the Abbott BNP (P = 0.026) and the BNP RIA (P < 0.0001) but not the total-BNP assay. CONCLUSIONS We have developed the first assay that measures BNP1-32 in plasma without interference by proBNP. Analysis of larger patient cohorts is now required to compare the performance of this assay with current less specific assays for the diagnosis or prognosis of HF.

Download Full-text

Advances in Development and Application of Influenza Vaccines

Frontiers in Immunology ◽

10.3389/fimmu.2021.711997 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jidang Chen ◽

Jiehuang Wang ◽

Jipei Zhang ◽

Hinh Ly

Keyword(s):

Influenza A ◽

Viral Vectors ◽

Influenza Virus Infection ◽

Economic Loss ◽

Cross Reactivity ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Manufacturing Cost ◽

Different Types ◽

High Manufacturing Cost

Influenza A virus is one of the most important zoonotic pathogens that can cause severe symptoms and has the potential to cause high number of deaths and great economic loss. Vaccination is still the best option to prevent influenza virus infection. Different types of influenza vaccines, including live attenuated virus vaccines, inactivated whole virus vaccines, virosome vaccines, split-virion vaccines and subunit vaccines have been developed. However, they have several limitations, such as the relatively high manufacturing cost and long production time, moderate efficacy of some of the vaccines in certain populations, and lack of cross-reactivity. These are some of the problems that need to be solved. Here, we summarized recent advances in the development and application of different types of influenza vaccines, including the recent development of viral vectored influenza vaccines. We also described the construction of other vaccines that are based on recombinant influenza viruses as viral vectors. Information provided in this review article might lead to the development of safe and highly effective novel influenza vaccines.

Download Full-text