Influenza virus is a globally important respiratory pathogen which causes a high degree of morbidity and mortality annually. The virus is continuously undergoing antigenic change and thus bypasses the host's acquired immunity to influenza. Despite the improvement in antiviral therapy during the last decade, vaccination is still the most effective method of prophylaxis. Vaccination induces a good degree of protection (60-90% efficacy) and is well tolerated by the recipient. For those at risk of complications from influenza, annual vaccination is recommended due to the antigenic changes in circulating strains. However, there is still room for improvement in vaccine efficacy, long-lasting effect, ease of administration and compliance rates. The mucosal tissues of the respiratory tract are the main portal entry of influenza, and the mucosal immune system provides the first line of defence against infection. Secretory immunoglobulin A (SIgA) and IgM are the major neutralizing antibodies directed against mucosal pathogens. These antibodies work to prevent pathogen entry and can function intracellularly to inhibit replication of virus. This review describes influenza virus infection, epidemiology, clinical presentation and immune system response, particularly as it pertains to mucosal immunity and vaccine use. Specifically, this review provides an update of the current status on influenza vaccination and concentrates on the two main types of influenza vaccines currently in use, namely the cold-adapted vaccine (CAV) given intranasally/orally, and the inactivated vaccine (IV) delivered subcutanously or intramuscularly. The commercially available trivalent IV (TIV) elicits good serum antibody responses but induces poorly mucosal IgA antibody and cell-mediated immunity. In contrast, the CAV may elicit a long-lasting, broader immune (humoral and cellular) response, which more closely resembles natural immunity. The immune response induced by these two vaccines will be compared in this review.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.0300-9475.2004.01382.x

Influenza Virus: Immunity and Vaccination Strategies. Comparison of the Immune Response to Inactivated and Live, Attenuated Influenza Vaccines

To identify immunological predictors of resistance to influenza A infection and illness, the immunological status of live and inactivated virus vaccines subsequently challenged with H1N1 or H3N2 wild-type virus was examined. We refer to prechallenge antibodies of vaccinees receiving live attenuated virus as infection induced and those receiving inactivated virus as inactivated vaccine induced. Inactivated vaccine-induced protection against wild-type virus infection or illness correlated with the level of neuraminidase-inhibiting antibody in serum, local hemagglutinin immunoglobulin G (IgG) (but not IgA) enzyme-linked immunosorbent assay antibody, and hemagglutination-inhibiting antibody in serum. In contrast, infection-induced resistance to wild-type virus infection correlated with local hemagglutinin IgA antibody and neuraminidase-inhibiting antibody in serum, but not with hemagglutination-inhibiting antibody in serum. These observations suggest that live vaccine virus infection-induced and inactivated vaccine-induced immunity may involve different compartments of the immune system; sufficient antibody in either serum or nasal secretions is capable of conferring resistance.

https://jcm.asm.org/content/jcm/24/1/157.full.pdf

Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus.

Context Influenza virus is a major cause of illness, disruption to daily life,
and increased use of health care in all age groups. Objective To assess the safety and effectiveness of intranasally administered
trivalent, live, attenuated influenza virus (LAIV) vaccine for reducing illness,
absenteeism, and health care use among healthy, working adults. Design Randomized, double-blind, placebo-controlled trial conducted from September
1997 through March 1998. Setting Thirteen centers across the United States. Participants A total of 4561 healthy, working adults aged 18 to 64 years recruited
through health insurance plans, at work sites, and from the general population.
 Intervention Participants were randomized 2:1 to receive intranasally administered
trivalent LAIV vaccine (n=3041) or placebo (n=1520) in the fall of 1997. Main Outcome Measures Episodes of febrile illness, severe febrile illness, febrile upper respiratory
tract illness, work loss, and health care use during the peak and total influenza
outbreak periods, and adverse events. Results Recipients of LAIV vaccine were as likely to experience 1 or more febrile
illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine
vs 14.6% for placebo; P=.19). However, vaccination
significantly reduced the numbers of severe febrile illnesses (18.8% reduction;
95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract
illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination also led to
fewer days of illness across all illness syndromes (22.9% reduction for febrile
illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work
lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile
upper respiratory tract illnesses), and fewer days with health care provider
visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for
febrile upper respiratory tract illnesses). Use of prescription antibiotics
and over-the-counter medications was also reduced across all illness syndromes.
Vaccine recipients were more likely to experience runny nose or sore throat
during the first 7 days after vaccination, but serious adverse events between
the groups were not significantly different. The match between the type A(H3N2)
vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2])
for the 1997-1998 season was poor, suggesting that LAIV provided substantial
cross-protection against this variant influenza A virus strain. Conclusion Intranasal trivalent LAIV vaccine was safe and effective in healthy,
working adults in a year in which a drifted influenza A virus predominated.

/pdf/effectiveness-of-live-attenuated-intranasal-influenza-virus-4wf17z0b27.pdf

Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial.

The report of the Institute of Medicine's Committee on Emerging Microbial Threats to Health in the United States, published in 1992, defines influenza virus as the prototype emerging infection (1). Pandemics of influenza have been recognized since earliest recorded history and, because of the mutability of the virus, still represent a formidable threat to the health of the nation. Although much progress has been made in describing the molecular aspects of the virus, in elucidating the epidemiology and modes of spread, and in developing methods for prevention and treatment, a rational strategy for control has not been established. The trends of modern society, including the increasing availability of rapid human transportation and the urbanization of the rapidly expanding human population, tend to facilitate the spread of influenza and increase morbidity. Modern medicine can reduce the mortality that resulted from complications of infection with influenza virus during earlier epidemics, but the cost of medical interventions has increased to the point that effective methods of epidemic control should be considered. This challenge provides an opportunity to develop, test, and have in place a strategy for control of interpandemic influenza before the next pandemic. Pandemics result from the emergence of an influenza A virus that is novel for the human population. Evidence for recycling of subtypes of influenza A after intervals of 60 years or more has been derived by determining antibody prevalence in elderly populations prior to the emergence of subtypes H2N2 in 1957 and H3N2 in 1968 (2, 3). A more ominous threat is the reservoir of 14 influenza A subtypes that persist in avian hosts (4). An avian virus can reassort with a human virus, as occurred in 1957 and 1968, to allow the creation of progeny that possess novel surface antigens with the potential to spread in human popu-

Emerging Infections: Pandemic Influenza

The purpose of this article is to review the nature of the immune response to influenza virus both in hosts which experience natural infection, particularly man, and in hosts which are experimentally infected, particularly mice, Until recently, an article on this topic may well have contained only a rather superficial account of the properties of the virion with hardly a mention of the replication process. However, the past few years have seen great advances in two almost separate developments. On the one hand, detailed information is now available on the viral genome and the expression of viral proteins: there are complete amino acid sequences and X-ray crystallographic analysis of the two surface glycoproteins, the hemagglutinin and the neuraminidase; we have a greater understanding of the roles of gene reassortment and mutation in the generation of antigenic shift and drift, and of the mechanism of viral replication and assembly. On the other hand, and although there are still very significant gaps, there has been a great increase in our knowledge of the different classes of lymphocytes, particularly T cells, and to a lesser extent of other cell types involved in the immune response to this virus. Significant correlations in the case of human studies and the findings from cell transfer studies in experimental systems have made possible the allocation of particular roles to different cell types.

Marylou Clements

Papers

Advantage of live attenuated cold-adapted influenza A virus over inactivated vaccine for A/Washington/80 (H3N2) wild-type virus infection.