Types A and B are responsible for seasonal epidemics. Production takes roughly six months 16 and during this time a new strain can arise, leading to a mismatch between the vaccine and circulating strain. Production of quadrivalent vaccines is an improvement, reducing the risk of mismatch of B strains. A suggested working model of how live attenuated influenza vaccine LAIV elicits immune response.
The numbers in the figure refer to 1. Viral influenza antigen is transported to the tonsils by dendritic cells DCs ; 4. Activation and proliferation of T cells IL-2 ; 5. Activation and proliferation of B cells, affinity maturation and isotype switching; 6. Activated B and T cells homes to site of infection vaccination ; 7. Plasma cells secrete specific mucosal antibodies and 8.
Plasma cells secrete specific antibodies into circulation. Adapted from. Although fatal cases of influenza occur in the elderly, children are the main transmitters of disease in the community, and most often hospitalized during outbreaks; often without influenza as suspected diagnosis.
The UK introduced seasonal LAIV into their childhood vaccination program 4—11 years old in and has estimated large national cost savings by vaccinating children with a reduction in morbidity due to herd immunity.
The WHO has published guidelines for the recommendation of seasonal influenza vaccines to the population at most risk of severe or fatal disease Table 1. A comparison of the immune responses after natural infection, and immunisation with inactivated influenza vaccine IIV or live attenuated influenza vaccine LAIV.
Table 1 is adaped from. By mimicking natural infection, but without causing disease or onward transmission, LAIV elicits both humoral and cellular immune responses Figure 1. Vaccines are given prophylactically to a healthy population including children. The tolerance of side effects is hence very low, and safety is of the utmost importance.
LAIV strains are safe, genetically stable, and do not revert to wild type viruses. Several studies have confirmed LAIV to be safe in children with intermittent wheezing and stable asthma, including children 18 months old. Although higher HI titers of or for H3N2 could be more appropriate for protection in children.
LAIV induces both humoral and cellular immune responses and there is an urgent need for new correlates of protection to evaluate the immunogenicity of LAIV in children, which may aid in development of new vaccines.
Mucosal antibodies are vital in protecting the upper airways, the site of viral entry, while serum antibodies generally protect the lower respiratory tract. LAIV elicits secretory IgA, which plays a major role in influenza protection being the predominant antibody secreted at the mucosal surfaces Figure 1.
Furthermore, local, mucosal IgA correlates with HI titers for all vaccine strains. Several studies have found that the highest humoral responses were directed towards the influenza B strains in LAIV. It may be due to lack of pre-existing immune responses to the B strain, but it could equally be due to differences in the infectivity of the LAIV strains, or that the B virus may be better adapted to replicate in humans. Unlike the HI, there exists no COP for mucosal antibodies, 73 due to great variations in quality and quantity and challenges in sampling and assaying of mucosal antibodies.
LAIV elicits both early and durable humoral and cellular immune responses in children. Increased numbers of Memory B cells MBCs as well as T-cellular responses, which were maintained for 6 months in most children, and up to one year in some children, have been found. It is debated whether LAIV is effective in older age groups, probably as pre-existing immunity derived from previous natural infection limits replication of the LAIV viruses. Children's developing immune system, combined with the impact of previous exposures priming to influenza may influence the age-related response to LAIV.
Age dependent differences are found in the response, supporting immunization of the youngest children with two doses, although most respond after the first dose. Serum IgG levels correlate with resistance to infection. The effect of previous priming on the subsequent LAIV immunological response is unclear.
The need for two doses of LAIV in young children is based on the belief that priming is essential. This is supported by a study where antibody titers were higher although not significantly boosted post-LAIV in children with pre-existing antibodies, indicating that LAIV perhaps assisted maintenance of the response. Tonsils are secondary lymphoid tissue, located at the site of entry of the upper respiratory tract, draining the oral and nasal cavities 87 and are an important induction site and reservoir for B-and T-cells.
Furthermore, MBC levels correlated with systemic antibodies HI , indicating that responses in the tonsils are reflected in the peripheral blood, which has earlier been observed for ASC numbers after IIV.
T-cells are critical for the control of viral infections, and may protect from severe illness or fatal outcome. Natural infection provides the basis for cross-reactive T-cells, and historical studies provide evidence of hetero-variant protection after influenza infection. Although advancements have been made, the precise immunological events that ultimately produce long lasting and neutralizing antibodies or cross-reacting T-cells remains unclear.
To design better vaccines, it is essential to better understand these complex immune responses induced by natural infection. Future research studying the immune responses after infection and LAIV vaccination will help answer some of these questions. Studying the responses in primed children could aid in development of improved future seasonal vaccines. The recent licensure of a quadrivalent LAIV is an improvement, protecting from both influenza B lineages.
The key to such a success lies in identifying conserved epitopes that exist in multiple influenza viruses including highly conserved HA stalk, or T-cell epitopes followed by developing a vaccine, which elicits a durable effective immune response. Larger studies will be needed to confirm the level of protection, and studies into the differences between US and European LAIV efficacy data are warranted as well.
There are no vaccines today, which are licensed on the basis of limiting severe disease. In the future, such a vaccine could prove valuable in reducing severe illness and the burden on healthcare systems from a novel virus and buy time before a specific vaccine is available. We wish to thank Dr. Karl A Brokstad for valuable scientific input and for providing the illustration in Figure 1. National Center for Biotechnology Information , U.
Journal List Hum Vaccin Immunother v. Hum Vaccin Immunother. Published online Jan 3. Kristin G. Author information Article notes Copyright and License information Disclaimer. Rebecca Jane Cox on. This article has been cited by other articles in PMC. Introduction Influenza viruses are a major cause of severe respiratory illness, and annually causes global fatality rates of ,—, people, with an estimated 3—5 million hospitalizations.
Influenza ecology Influenza is an RNA virus, lacking accurate proof reading mechanisms. Open in a separate window. Figure 1. Influenza vaccination strategies Although fatal cases of influenza occur in the elderly, children are the main transmitters of disease in the community, and most often hospitalized during outbreaks; often without influenza as suspected diagnosis.
Table 1. Vaccine safety Vaccines are given prophylactically to a healthy population including children. The early kinetics of the mucosal immune response Mucosal antibodies are vital in protecting the upper airways, the site of viral entry, while serum antibodies generally protect the lower respiratory tract. The effect of priming on the subsequent immune response It is debated whether LAIV is effective in older age groups, probably as pre-existing immunity derived from previous natural infection limits replication of the LAIV viruses.
Tonsil responses after LAIV Tonsils are secondary lymphoid tissue, located at the site of entry of the upper respiratory tract, draining the oral and nasal cavities 87 and are an important induction site and reservoir for B-and T-cells.
T-cell immune responses after LAIV vaccination T-cells are critical for the control of viral infections, and may protect from severe illness or fatal outcome. The possibility of heterosubtypic protection Natural infection provides the basis for cross-reactive T-cells, and historical studies provide evidence of hetero-variant protection after influenza infection.
Future perspectives Although advancements have been made, the precise immunological events that ultimately produce long lasting and neutralizing antibodies or cross-reacting T-cells remains unclear.
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed. Acknowledgments We wish to thank Dr. References 1. WHO Fact sheet about seasonal influenza. Stohr K. Influenza—WHO cares. Learn More. Serum samples collected from 18 volunteers 1, 2, and 3 months after vaccination with Cendehill strain of attenuated rubella virus vaccine were fractionated on a Sephadex G column to test for immunoglobulin M IgM antibody.
Seventeen of the 18 had demonstrable IgM antibody in serum collected 1 month postvaccination whereas only 5 and 3 had IgM antibody 2 and 3 months, respectively, post-inoculation. The geometric mean titers of hemagglutination-inhibiting antibody in the 19 S fraction were 38, 7, and 6 at 1, 2, and 3 months after vaccination, whereas the corresponding 7 S titers were 29, 53, and 57, respectively. Four other seronegative volunteers vaccinated with Cendevax were tested serially for total antibody only in whole blood obtained by finger pricks.
Three of them showed appearance of antibody between 14 and 17 days and one between 17 and 21 days. It appears that vaccine-induced immune response is similar to natural infection especially with regard to the time of appearance of antibody and the relative proportions of IgM and IgG antibody thus produced.
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Links to PubMed are also available for Selected References. These references are in PubMed. This may not be the complete list of references from this article. National Center for Biotechnology Information , U. Journal List Infect Immun v. Infect Immun. Cytokine expression was determined using Q-PCR. Data are presented as fold of increase compared to mock infected. Myd88 signaling is partially involved in induction of higher innate cytokine production and during NS4B P38G mutant infection.
The development of safe and effective vaccines against WNV remains a high priority. An ideal candidate WNV vaccine requires greatly reduced potential for neurovirulence, neuroinvasiveness, and restricted virus replication, while still having the ability to induce a robust protective immune response. Live attenuated vaccines have traditionally induced the best protective immune responses, but most have been derived empirically. Several approaches to attenuate WNV have been reported, including a capsid deletion mutation attenuated strain [ 35 ] and mutations in E and NS proteins for chimeric vaccine [ 36 ].
Further characterization of immune response to the attenuated WNV strains, including both innate and adaptive immunity are important steps in understanding their protective mechanisms.
In this study, we have shown that this NS4B P38G mutant had a lower viremia and no lethality in mice following systemic infection in B6 inbred mice. Finally, despite of the lower viremia and no lethality during primary infection of P38G NS4B mutant, all surviving mice were protected from a secondary challenge with LD of wild-type WNV.
NS4B P38G mutant infection in all in vitro and in vivo infection studies were consistently shown to have small-plaques and non-neuroinvasive phenotypes. Reversion at NS4B was never detected, suggesting genetic stability. Overall, these results suggest that the NS4B P38G mutation has a high potential for contribution to a future vaccine candidate. During an acute viral infection, such as WNV, T cells go through three distinct phases involving initial activation and expansion effector T cell , a contraction or death phase, and the establishment and maintenance of memory memory T cell [ 42 ].
Future investigation will continue to focus on the role of the individual cytokine in memory T cell development during WNV infection. This is consistent with recent reports by others [ 17 , 34 ].
This is consistent with the hypothesis that Myd88 signaling may be required for induction of proinflammatory cytokine production by NS4B-P38G mutant infection. These results may provide critical insights for new strategies in improving the efficiency of future attenuated flavivirus vaccines to generate long-lasting protective immune responses.
T cell response at the later stage of WNV infection. Data presented are representative of two similar experiments. We thank Drs. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
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The publisher's final edited version of this article is available at Vaccine. See other articles in PMC that cite the published article. Associated Data Supplementary Materials Suppl.
Introduction West Nile virus WNV , a mosquito-borne neurotropic pathogen, belongs to the family of Flaviviridae, the genus Flavivirus, a group of plus-sense, single-stranded RNA viruses [ 1 — 2 ]. Materials and methods 1. WNV Infection Mice were inoculated intraperitoneally i.
Flow cytometry Splenocytes were stained with antibodies for cell surface markers, including CD4 or CD8, e-Biosciences. Statistical analysis Data analysis was performed using Prism software Graph-Pad statistical analysis. Results 3. Open in a separate window. WNV specific antibody responses were not different between mice infected with these two viruses; all mice are protected from a secondary challenge with LD of wild-type WNV following primary infection with P38G mutant B cell-mediated humoral immune responses are critical for the host defense against disseminated infection by WNV [ 29 — 31 ] and might also contribute to a protective memory response.
NS4B-P38G mutant infection in primary DCs shows a reduced replication rate, but a higher level of innate cytokine production than wild-type virus partially dependent on Myd88 signaling DCs represent the most important antigen presenting cells APCs exhibiting the unique capacity to initiate primary T cell responses.
Discussion The development of safe and effective vaccines against WNV remains a high priority. Supplementary Material 01 Suppl. Click here to view. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. References 1. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. West Nile virus. Lancet Infect Dis. West Nile virus recombinant DNA vaccine protects mouse and horse from virus challenge and expresses in vitro a noninfectious recombinant antigen that can be used in enzyme-linked immunosorbent assays.
J Virol.
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