Influenza Vaccines and Vaccination Strategies

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Introduction

Influenza is a communicable acute respiratory disease and one of the major infectious disease threats to the human population. Influenza virus affects individuals of all ages, causes repeated infections throughout life, and is responsible for annual worldwide epidemics of varying severity, commonly referred to as “seasonal influenza.” Influenza also causes periodic pandemics that are characterized by a novel virus strain to which the majority of the population is susceptible and which have the capability of causing disease and sustained transmission from person-to-person.

This chapter focuses on seasonal influenza vaccines and vaccination programs. It provides an update on global influenza disease epidemiology and reviews the currently available influenza vaccines, the global recommendations for their use, and the programmatic challenges of delivering them.

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The influenza virus

There are 3 types of influenza viruses that infect humans—A, B, and C—which are classified based on immunologic and biologic properties. Influenza viruses are negative strand RNA viruses with a segmented genome—influenza A and B viruses contain 8 RNA segments, and influenza C contains 7 RNA segments. Type A influenza viruses are further classified into subtypes according to the combinations of the hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins. HA is the major envelope protein and is the protein against which most neutralizing antibodies are directed. NA is important for release of virus particles and viral spread from cell to cell. As of 2015, 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes have been identified and distinguished structurally and antigenically—H1 through H18 and N1 through N11, respectively. To date, H1, H2, and H3, and N1 and N2 have been found as components of epidemic viruses in humans. The influenza A subtypes currently circulating among humans are influenza A(H1N1) and A(H3N2).

Influenza B viruses are mainly, although not exclusively, found in humans and form a single antigenic group. Although the antigenic variation is well-established, influenza B viruses are not divided into subtypes. They are, however, further classified into lineages and strains. Currently circulating influenza B viruses belong to one of two lineages: B/Yamagata and B/Victoria. Type C viruses cause disease much less frequently than type A and B, are not believed to cause epidemics, and are not a target for influenza vaccines.

The influenza virus undergoes frequent antigenic change. When mutations occur in influenza virus HA and NA surface glycoproteins, they are able to evade immunity induced by infection to previously circulating strains. This is the basis for annual influenza epidemics and necessitates the frequent changes in vaccine composition. A more substantial antigenic change can occur through gene reassortment. As a segmented RNA virus, influenza may reassort with other human and nonhuman influenza viruses. When that gene reassortment occurs in such a way that the virus has major changes to the HA and/or NA antigens, yet retains the capacity to cause disease and transmit among humans, a new strain can emerge, for which immunity in the population is lacking. These reassortment events may create new pandemic influenza viruses that could cause substantial disease, including deaths, globally.

Avian, swine, and other animal influenza viruses may also directly infect humans, and to date human-to-human transmission of these viruses has fortunately been limited. Clearly, these viruses in animals need to be closely monitored, as the human population has little immunity to them. If animal influenza viruses were to ever efficiently transmit from person-to-person, there would be the potential for a severe influenza pandemic. Because there are many animal reservoirs for influenza, eradication of the influenza virus is not a viable control option.

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Influenza disease and burden of illness

Influenza virus infection can result in a spectrum of illness from asymptomatic infection, upper respiratory tract illness with or without fever, lower respiratory tract illness, exacerbation of cardiopulmonary disease, secondary bacterial infection, and progression to severe respiratory failure and death. Classic influenza illness is characterized by a sudden onset of fever, and respiratory symptoms such as cough, sore throat, runny nose, or earache. Systemic symptoms such as headache, muscle and joint pain, and malaise are common. For clinical studies and surveillance purposes, “influenza-like illness” is frequently defined as the sudden onset of fever or feverishness with cough and/or sore throat. Most people recover from influenza illness within a week without requiring medical attention, although the cough may be more prolonged and last for several weeks. However, a subset of individuals develops serious and sometimes fatal disease.

Because influenza symptoms are nonspecific, a definitive diagnosis of infection requires laboratory diagnosis. For example, influenza virus infection could resemble infection by any number of respiratory viruses. Further, influenza may cause nonrespiratory diseases such as nonspecific febrile illness in infants, febrile seizures in children, as well as encephalitis, myositis, and myocarditis/pericarditis in all age groups. Clinicians, researchers, and policy makers often underestimate the incidence of severe influenza due to the underutilization of influenza-specific diagnostic tests.

In general, influenza virus infection is most common in children, while severe complications of influenza virus infection are most common among young children, the elderly, pregnant women, persons of all ages with underlying medical conditions (such as chronic heart or lung disease), and persons with immunosuppressive conditions. While studies conducted in temperate, developed-country settings largely determined these risk conditions, studies have confirmed many of the same factors to be associated with severe disease in Bangladesh and Thailand. Furthermore, there may be additional risk factors associated with severe disease particular to developing-country settings, such as crowding, prevalence and spectrum of chronic illness including HIV, malnutrition, and low birth weight, proximity and proportion of the young to the elderly, and environmental exposures.

In areas where it has been studied, influenza deaths are most frequent in older adults. From 1976 through 2007, a yearly average of 21,098 influenza-related deaths occurred among United States adults 65 years and older. During the period from 1998 to 2005, age-standardized excess mortality among the elderly in South Africa were even higher than in the United States. Importantly, deaths due to influenza may occur at any age. In South Africa, a substantial burden of influenza mortality has been estimated in children younger than 1 year of age, and in HIV-positive persons of all ages. In South Africa, 28% of influenza-associated deaths at any age occur among HIV-positive individuals, which has important implications for other parts of Africa with high HIV prevalence.

Deaths can increase during pandemic periods when a population has no preexisting immunity to the virus. In the United States, between 37 and 171 children in the United States died each year from laboratory-confirmed influenza infection during annual epidemics between 2004 and 2015, as compared to 300 laboratory-confirmed pediatric deaths during the 2009–2010 H1N1 influenza pandemic. These are certainly underestimates given the underutilization of diagnostic testing. The 1918 influenza A (H1N1) pandemic is estimated to have caused 50 to 100 million deaths worldwide. Even so, the cumulative mortality from seasonal influenza exceeds that of pandemic influenza in the United States, and likely throughout the world.

While countries with temperate climates have conducted intensive influenza surveillance and clinical/epidemiologic research for more than 50 years, influenza in tropical and subtropical climates has been understudied. The World Health Organization (WHO) Global Influenza Surveillance Network has coordinated pandemic planning efforts and influenza surveillance activities since its creation in 1948. During most of this time, influenza surveillance was focused on the collection of virus isolates to inform the influenza vaccine strain selection, with activities mainly concentrated in developed, temperate countries. Since the emergence of avian influenza A (H5N1) in 1996 and the subsequent concern about an imminent pandemic, the global community has strengthened influenza surveillance and research capacity in tropical developed and developing regions around the globe. The increasing availability and use of reverse transcription polymerase chain reaction (RT-PCR) diagnostic techniques has revealed much higher rates of influenza virus infection in developing-country settings than had been demonstrated in prior studies that used less sensitive diagnostic tests. The 2009 influenza A (H1N1) pandemic led to a further intensification of influenza surveillance and research in developing country settings.

In temperate and subtropical regions, influenza spreads in seasonal epidemics that coincide with the winter season. In tropical regions, many countries have reported peaks in influenza activity associated with rainy and cold seasons and either longer epidemics or year-round transmission. While attack rates vary substantially by season and locale, influenza typically infects up to 10% of adults and 30% of children each year in temperate regions. Epidemics can result in high levels of worker/school absenteeism and productivity losses. Furthermore, closed populations such as schools, hospitals, and isolated communities may experience much higher attack rates. School-aged children play an important role in the spread of influenza viruses.

Available data are incomplete to estimate influenza incidence in most tropical regions. Recent influenza vaccine studies in pediatric age groups in Senegal and Bangladesh, for example, have revealed attack rates similar or higher than those seen in the United States. Even higher attack rates have been noted in certain circumstances. For example, investigations of seasonal influenza outbreaks estimated attack rates of clinical infection to be 67% in Madagascar in 2001 and 47% in Democratic Republic of Congo in 2002. While much is known about influenza transmission dynamics in temperate regions, many factors in developing regions may alter disease activity where household, community, environmental, and host factors may differ.

Worldwide, the WHO estimates 3 to 5 million cases of severe illness, and about 250,000 to 500,000 deaths associated with annual influenza epidemics. A 2011 Lancet meta analysis in children younger than 5 years of age estimates 20 million (95% CI 13-32) acute lower respiratory infections (ALRI) associated with influenza, including 1–2 million cases of severe ALRI. This study estimated 28,000–111,500 influenza-attributable deaths annually, with 99% of early childhood influenza deaths occurring in low- and middle-income countries.

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Influenza vaccines

Immunization against influenza serves as the primary means for preventing influenza illness. An unprecendented number of influenza vaccines are available on the global market. ( Fig. 21.1 ). The currently available vaccines are targeted to the HA and NA glycoproteins of the virus, and thus must be reformulated frequently due to the circulating virus propensity to mutate at key antigenic sites. The strains included in the vaccine are selected based on information derived from globally coordinated epidemiologic and virologic surveillance— WHO’s Global Influenza Surveillance and Response System (GISRS). The GISRS monitors the evolution of influenza viruses and the emergence of influenza viruses with pandemic potential. Twice a year, WHO convenes technical consultations (vaccine composition meetings) to recommend the viruses to be included in influenza vaccines that are termed Northern and Southern Hemisphere formulations. All current vaccines are recommended to contain the selected Influenza A (H1N1) and A (H3N2) strains, and either one (trivalent) or two (quadrivalent) influenza B viruses. Quadrivalent vaccines were developed to protect against both B lineages currently in circulation in humans, as it has been difficult to accurately predict the predominantly circulating influenza B virus lineage. Further, in many parts of the world, both lineages have cocirculated.

Currently, two general classes of influenza vaccines are licensed for production globally: parenterally administered non-replicating virus vaccines and intranasally administered live attenuated vaccines. The non-replicating vaccines may be further divided into manufacturing substrate (eggs, cell culture, fully recombinant), route of administration (intramuscular, intradermal) type of preparation (whole virus, split virus, and subunit vaccines) and by presence of adjuvant (MF-59) ( Table 21.1 ).

The availability of licensed influenza vaccine products is dependent on the age and health status of the individual. For children younger than 6 months of age, there are no currently approved influenza vaccines anywhere in the world. For children younger than 2 years of age, nonadjuvanted inactivated vaccines are the only approved vaccines in most places, although Canada has approved an adjuvanted inactivated vaccine for children from 6 through 23 months of age. For children 2 years of age and over, both nonadjuvanted, inactivated and live-attenuated vaccines are approved and available. The options increase for adults, as intradermal and recombinant vaccines are licensed beginning at 18 years of age. For adults 65 years and over, a high dose inactivated vaccine is available in the United States, while Europe, Canada, and the United States have approved an MF-59 adjuvanted vaccine for this group ( Table 21.1 ).

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Non-replicating influenza vaccines

Inactivated influenza vaccines (IIVs) were first licensed for broad use in 1945. The 15 microgram HA per antigen component of IIVs was determined by consensus in the 1970s after improvements in quantification methods. Only recently has the antigen content of such vaccines been altered to optimize immune response in certain populations, for example, higher antigen content vaccines for the elderly, higher antigen content in the recombinant vaccine, and reduced antigen content in intradermal vaccines.

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Safety of non-replicating vaccines

IIVs have been in use for 70 years, and as a class they have a robust safety profile, as determined in clinical trials as well as large postlicensure surveillance programs. Product-specific information is less available, and the safety databases for the newer products will be more limited until use of the products increase. In general, the most common adverse events associated with IIVs are local injection site reactions. However, more serious adverse events have been recognized and are described more specifically below.

In children, across multiple large studies, IIVs are generally considered to be safe for all ages and all risk groups. In clinical trials, fever and injection-site reactions are the most common events, and tend to be mild and transient. In 2010, a IIV-trivalent (IIV-T) formulation from a single manufacturer in Australia was strongly associated with increased febrile seizures in children. This led to varying recommendations in countries precluding the use of this vaccine in younger children, and enhanced surveillance for febrile seizures in the United States and elsewhere. The febrile seizure risk among children in the United States was noted to be elevated in some years and not others, and more so when IIV was coadministered with PCV-13 vaccines. In all cases the risk for febrile seizures in the United States was determined to be substantially lower than observed in 2010 in Australia.

Likewise, in adults, IIVs have a strong safety record. In placebo-controlled trials, only injection site soreness is consistently associated with receipt of IIVs. The adjuvanted IIVs and newer high-dose vaccines are associated with increased injection site reactions and mild systemic events, although these are generally mild and transient. Safety of IIVs has also been well-studied among pregnant women, again realizing a general lack of product-specific and limited randomized clinical trial data.

Safety surveillance in pregnancy is particularly challenging, as the background incidence of rare pregnancy-related adverse events is not well-established, particularly in low resource countries. However, multiple studies to date have not identified consistent, unexpected serious acute events, adverse pregnancy outcomes, or congenital anomalies associated with receipt of influenza vaccine during pregnancy.

The oculorespiratory syndrome (ORS) is an acute, self-limited reaction associated with bilateral red eyes, facial edema and/or respiratory symptoms such as coughing, wheezing, hoarseness, sore throat, chest tightness or difficulty breathing occurring within 2–24 h of receiving IIV. It is more common in adults and in women. It was first described in Canada in the 2000–2001 influenza season and was strongly associated with one specific preparation manufactured in Quebec. Subsequently, enhanced surveillance did identify lesser associations with other vaccines in Canada, the United States, and Europe. While the pathogenesis is not known, it is not IgE-mediated. Thus, persons with previous ORS may be safely revaccinated if IgE hypersensitivity events can be excluded.

Individuals with egg allergy may experience hypersensitivity reactions after receipt of influenza vaccines given the residual egg protein that may exist in most vaccines. While the cell culture-based vaccines do not use eggs in the manufacturing process, influenza seed viruses are passaged in eggs so very small amounts of residual egg proteins may still remain in cell culture vaccines. The new recombinant vaccine, FluBlok, is the only product to be entirely egg-free. Thus, the risk for reaction in egg-allergic individuals will vary based on the product and the individual’s history, and the manufacturer’s package insert and country-specific recommendations should be consulted.

In 1976, there was concern in the United States regarding an imminent swine influenza pandemic, which resulted in mobilization of public health resources and development of a specific vaccine. The swine influenza vaccine was associated with an increased frequency of Guillain–Barre syndrome (GBS), an acute inflammatory polyneuropathy. No subsequent study of influenza vaccines and GBS has demonstrated a risk of the magnitude seen in 1976, which was estimated at one additional case of GBS per 100,000 persons vaccinated. While not consistently noted, studies have identified risks on the magnitude of 1 additional case of GBS per 1 million persons vaccinated, such as the 1992–93 and 1993–94 seasons in the United States. Multiple studies during other seasons have identified no association.

During the 2009 pandemic, several countries demonstrated an increased risk of narcolepsy following receipt of ASO3-adjuvanted influenza vaccine in children, adolescents and young adults. The ASO3 adjuvant is in the oil-in-water adjuvant class, and is not approved for use in any seasonal influenza vaccine. MF-59 is also an oil-in-water adjuvant. MF59 adjuvanted seasonal influenza vaccines have not been associated with narcolepsy.

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