Influenza vaccination

Influenza is an acute and highly contagious viral infection with worldwide distribution. The influenza "season" is a period of 8-10 weeks during which 80% of influenza outbreaks occur, with the specific time frame varying by region, but generally ranging from late fall to early spring in temperate zones of both hemispheres. These seasonal epidemics are caused by the frequent antigenic drifts of the pathogen, which also serve as a virological driver for annual vaccine development and deployment (Lamb RA et al. 2001; Cox NJ et al. 1999). The influenza virus causes an acute febrile illness with severity ranging from mild to very severe and in some cases leading to death. The highest risk of a clinically severe course of the infection is for children < 5 years of age, older people, pregnant women and people with underlying chronic illnesses. The morbidity associated with influenza is associated with an increase in healthcare utilization, e.g. outpatient visits, hospitalizations and mortality, especially in high-risk groups.

The World Health Organization (WHO) estimates that around 5-15% of the population falls ill with influenza each year. The annual global burden of influenza is estimated at almost 1 billion infected people, 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths. Most flu-related deaths in industrialized countries occur in older people aged 65 and over. According to the European Center for Disease Prevention and Control (ECDC), seasonal influenza causes 40 to 50 million symptomatic cases in the European Union (EU)/European Economic Area (EEA) each year, and 15,000 to 70,000 people die as a result of influenza. In healthy adults, seasonal influenza generally does not cause serious infections, but for older people the infection poses a serious health risk. The risk of influenza-related mortality increases sharply after the age of 65 (Rothberg MB et al. 2008).

A study conducted in Israel examined age-specific mortality during the 1999-2006 influenza season. The overall mortality rates in this study ranged from 7.7 to 36.1 / 100,000 for all causes and from 4.4 to 24.4 / 100,000 for respiratory and circulatory diseases. Influenza-associated deaths from respiratory and circulatory diseases ranged from 280 to 1516 per year; importantly, about 90% of deaths occurred in persons over 65 years of age, while only about 1% occurred in persons under 50 years of age (Linhart Y et al. 2011).

Impact on vaccine efficacy: An efficient immune response depends on functional cell signaling pathways to coordinate the complex interactions between the innate and adaptive immune systems. Impaired processing and presentation of antigens reduces the immune response in the elderly (Goodwin K et al. 2006). Cellular signaling pathways that are disrupted by aging include migration of antigen-presenting cells, antigen presentation by dendritic cells, and cytokine production. Signs of poor antibody recruitment include decreased IgA and IgG levels, delays in reaching peak titers, and a rapid decline in antibody concentrations. In individuals aged ≥ 75 years, seroprotection against influenza is only 29-46%, compared to 41-58% in 60-74 year olds (Weinberger B et al. 2008). Furthermore, a shift from pro-inflammatory Th1 cytokines to the more anti-inflammatory Th2 cytokines may be correlated with a reduced cytotoxic T lymphocyte (CTL) response and an impaired response to the influenza vaccine. The reduced humoral response is thought to be due to dysfunction of naive, aged CD4+ T helper cells and reduced support from follicular T cells. Although specific T cell responses are impaired in the elderly, CTL recruitment may serve as a better indicator of protection against influenza than a simple measurement of antibody concentration.

Immune response to infection in the elderly: With increasing age, innate and adaptive immune responses gradually deteriorate, resulting in a reduced ability to respond to infection and vaccination. The immunogenicity of a vaccine is defined as "the strength or magnitude of an immune response" (Center for Disease Control and Prevention Vaccine effectiveness 2017).

Innate response: With increasing age, the initial innate response of neutrophils and macrophages is characterized by decreased phagocytic activity and reduced oxidative burst. Toll-like receptors (TLRs), transmembrane proteins on phagocytic cells, provide an important link between the innate and adaptive response by recognizing non-self proteins and triggering the intracellular signaling pathways that mediate the antigen-specific response. In macrophages of the elderly, defects in TLR expression impair this critical response (Renshaw M et al. 2002). In addition, epithelial cells provide an important structural and immunological barrier to pathogens, but the number of Langerhans cells in the skin declines with age (Grewe M 2001). Taken together, these age-related impairments of the innate immune response reduce antigen uptake at the injection site and reduce the immunogenicity of the vaccine.

Adaptive response: The adaptive response depends on the rapid recognition of foreign antigens and is mediated by antigen-presenting proteins in cell membranes, such as major histocompatibility complex (MHC) class I and II cells. The MHC class I complexes in the membranes of nucleated cells interact with cytotoxic T cells; the MHC class II proteins in antigen-presenting cells (e.g. B cells, macrophages and dendritic cells) interact primarily with helper T cells. The MHC class II cells present antigen fragments on the cell surface to CD4+ T lymphocytes, but the upregulation of these cells is impaired by aging. A reduction in antigen presentation by dendritic cells has been demonstrated in both animal models and human studies (Grewe M 2001)

Despite methodological discrepancies between meta-analyses of seasonal vaccines for older people, most influenza vaccines show statistically significant efficacy within a highly variable range. The WHO and ECDC agree that targeting older people, defined as those aged 65 years and older, is a sound strategy to prevent adverse outcomes from influenza. Many countries therefore recommend annual influenza vaccination for older people and risk groups such as people with pre-existing medical conditions and pregnant women.

There are no universal recommendations for the definition of "elderly". Many countries use the age of 65 as a criterion, while others refer to the age of 50 or 60. Nevertheless, the recommendation to vaccinate older people is an essential part of almost all influenza vaccination strategies.

Despite the fact that recommendations have been developed and implemented in most industrialized countries for decades, influenza cannot be eradicated for several reasons. Firstly, most bird species and pigs are natural hosts for influenza A viruses. They support the circulation and reassortment of influenza A, making it impossible to break this cycle. In addition, the influenza virus is particularly prone to changing its antigenicity, so annual vaccine boosters are required.

Practical recommendation: When should I be vaccinated? The best time to get the flu vaccine is before the flu season, more precisely before the start of influenza activity in the population. It is usually recommended to be vaccinated against influenza by the end of October, but vaccination in December or later could also be beneficial, especially for older people.

In fact, flu vaccines are generally well tolerated and safe in older people. Serious and clinically important adverse events following vaccination are rare in the elderly. Most adverse events resolved within 3 days.

The most common local reactions are pain, redness, swelling and induration. In the large clinical trial in the Netherlands, 23% of patients aged 60 years and older reported one or more adverse reactions, compared to 14% who received a placebo. The route of administration may influence the occurrence of adverse events. The incidence of injection site reactions was higher after intradermal vaccination than after intramuscular vaccination.

The most common systemic reactions reported in the elderly (65 years or older) within 7 days of influenza vaccination were malaise (7.2%), fever (5.7%), cough (6.6%), rhinitis (13.2%) or nausea (4.5%).

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Influenza is a vaccine-preventable disease. The first influenza vaccines were developed, tested and used in the 1930s and 1940s, and in Europe since the 1960s. The vaccines are registered and licensed for use in older people as trivalent or quadrivalent vaccines with and without adjuvant. Trivalent influenza vaccines contain an A(H1N1)-like influenza virus, an A(H3N2)-like influenza virus and a B-like influenza virus. The adjuvanted trivalent inactivated influenza vaccine MF59 is licensed for persons aged ≥ 65 years. Quadrivalent vaccines contain an additional virus strain, a B-like virus. Every year in February and September, the World Health Organization (WHO) makes recommendations on which viruses will be included in the flu vaccines for the coming flu season in the northern and southern hemispheres.

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