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

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.

The immune response to influenza infection.

Mice previously infected with an aerosol of A/Rec 31 influenza virus were strongly protected against an aerosol challenge with A/Vic influenza as judged by lung virus titers recovered 2 days after the challenge infection. Such complete homotypic immunity was not achieved by priming with live Rec 31 virus injected i.v. or UV-inactivated Rec 31 virus administered s.c. together with Al(OH)3 and saponin. The reason for the superior protective effect of the natural infection was investigated. The protection induced by respiratory infection with Rec 31 virus was specific for influenza A viruses. It was not correlated with specific serum hemagglutination inhibition antibody titer or cross-reactive cytotoxic T (Tc) cell reactivity. Moreover, the transfer of splenic and lymphoid T cell populations with strong secondary Tc activity did not significantly reduce lung virus titers in recipient mice 3 days after infection. The protection however occurred in parallel with the presence of cross-reactive IgA antibody in the lung washings. It thus appears that local secretory IgA plays a causal role in the prevention of cross-infection by influenza A virus. Serum antibody and Tc cells, on the other hand, may be crucial for recovery from such infection. All mice primed with live Rec 31 virus, administered i.v. or by aerosol and expressing equally high levels of Tc reactivity, survived a lethal challenge with A/PR8 virus. The same challenge, however, killed half of the mice immunized s.c. with inactivated Rec 31 virus which induced only a low level of Tc reactivity.

Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity.

Human immune responses to influenza virus vaccines administered by systemic or mucosal routes.

Influenza A virus contains a negative-sense, single-stranded RNA genome which consists of 8 segments that code for 7 structural and 3 non-structural proteins (Murphy et al. 1985). In nature, the virus undergoes antigenic changes, referred to as antigenic drift and shift, that permit it to escape from immunity induced by prior infection with related influenza A viruses (Murphy et al. 1985). Common to both types of antigenic change are alterations in the surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA) (Murphy et al. 1985). Antibodies to the HA glycoprotein neutralize the infectivity of the virus, and antibodies to the NA prevent efficient release of virus from infected cells (Askonas et al. 1982; Becht et al. 1971). Passive transfer of monoclonal antibodies to the HA or NA glycoprotein protects mice from experimental challenge with wild type influenza virus whereas those to the membrane (M) protein or nucleoprotein (NP) fail to protect (Askonas et al. 1982). Clearly, the surface glycoproteins constitute the major protective antigens against which an immune response is directed. Immunization of animals with purified NP or with NP expressed by a vaccinia virus induces partial resistance to lethal wild type virus challenge, but the level of resistance is considerably less than that induced by immunization with HA (Andrew et al. 1986; Wraith et al. 1986). It is thought that the resistance induced by immunization with NP is mediated primarily by histocompatibility class I restricted cytotoxic T-cells, but is not limited to this T-cell subset (McDermott et al. 1987; Taylor et al. 1986).

The systemic and mucosal immune response of humans to influenza A virus.

An intranasal, inactivated trivalent influenza A vaccine containing 7 micrograms of A/Bangkok/1/79 (H3N2) hemagglutinin was administered to 20 children aged 1 to 6 years to assess the local and systemic immune responses to antigen delivered to the respiratory tract. Six children without prior influenza virus infection exhibited no local immune response and manifested only a minimal systemic response to the intranasal vaccine. In contrast, five individuals who were previously infected with a live attenuated influenza A H3N2 virus vaccine, although having no residual secretory antibody at the time of challenge, promptly developed a local antibody response to intranasal, inactivated antigen. Therefore, the live influenza A virus vaccine had induced memory in the local immunoglobulin A (IgA) immune system. The third group of nine children had previously been infected with wild-type H3N2 influenza virus. A majority of these children had residual local and systemic antibody at the time of challenge but they demonstrated some boosting of local IgA antibody with administration of intranasal inactivated vaccine. The competence of the secretory IgA immune system in young children in mounting primary and secondary responses to influenza antigens has important implications for approaches to prevention of influenzal illness.

https://iai.asm.org/content/iai/40/3/1092.full.pdf

D T Karzon

Papers

Secretory immunological response after intranasal inactivated influenza A virus vaccinations: evidence for immunoglobulin A memory.