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Inactivated and Recombinant Influenza Vaccines
HISTORY AND IMPORTANCE
History of the Disease and Vaccines
Influenza is a leading cause of morbidity and mortality worldwide, occurring in annual epidemics and occasional global pandemics. Five global pandemics of influenza with high attack rates have been well described, the first beginning in 1889, with subsequent pandemics occurring in 1918, 1957, 1968, and 2009. However, influenza pandemics and epidemics have likely occurred for millennia, with early mentions of what might have been epidemics by the 12th century and a pandemic of influenza in the 16th century. Isolation of the influenza A virus in 1933 rapidly led to the identification of influenza viruses as the cause of epidemics and pandemics of respiratory disease followed by the development, testing and first use of influenza vaccines in the 1930s and 1940s.
Early influenza vaccines were monovalent products developed primarily for use in military populations. In 1960, following the 1957–1958 pandemic, the United States (U.S.) Public Health Service first recommended seasonal influenza vaccines be given to nonmilitary persons that were known to have a high risk of influenza complications. Early monovalent vaccines were replaced with multivalent vaccines, acknowledging the cocirculation of influenza A(H3N2), A(H1N1) viruses and influenza B viruses, the need for type or influenza A subtype-specific immunization, and the unpredictability of strain prevalence from year to year. Most influenza vaccines used around the world are trivalent, containing influenza A(H1N1), A(H3N2) and one B lineage vaccine virus. In 2012, quadrivalent vaccines, including both B/Victoria/2/1987 (B/Victoria) and B/Yamagata/16/1988 (B/Yamagata) lineages, were first licensed in the U.S.
From the beginning, influenza vaccination programs were based on principles that remain relevant for modern vaccine programs. First, for the most part, the strategy of targeting high-risk groups for immunization against influenza became the standard paradigm for influenza vaccination programs and policies globally. With the notable exception of the U.S. decision to expand influenza vaccine policy to recommend annual vaccination for all persons ≥6 months of age (i.e., “universal vaccination”), other national influenza programs generally target specific persons who are at elevated risk of severe or complicated disease based on age, underlying disease or pregnancy status. , Second, until 2003 when the first live attenuated vaccine was approved, influenza vaccines have been produced from inactivated, purified influenza viruses grown in embryonated eggs inoculated with influenza viruses, and administered intramuscularly. While approaches to influenza immunization have expanded to include additional modes of delivery (e.g., mucosal delivery of live attenuated vaccines, intradermal injection) and approaches (e.g., recombinant protein vaccines, vaccines grown in cell culture, higher antigen dose and adjuvanted vaccines), the majority of influenza vaccines given worldwide remain inactivated injected vaccines. Third, because of continual genetic and antigenic changes in influenza viruses, influenza vaccines are continually updated with contemporary strains, and vaccine programs must target recipients annually to ensure protection against current strains. The requirement for annual vaccine formulation and production and for annual immunization campaigns makes influenza vaccines unique and challenging.
Why the Disease Is Important
Seasonal influenza epidemics are associated with substantial disease burden each year worldwide in persons of all ages. Each year, an estimated 3–18% of persons have illness associated with influenza, although significant variability in rates of illness occur from year to year. Most infections lead to self-limited disease that does not result in a healthcare visit; however, severe complications resulting in hospitalization and death may occur, particularly in persons with certain underlying health conditions and among young children and older adults. Older adults account for most hospitalizations and deaths associated with influenza each year in the U.S.. , , As a result, influenza-associated illnesses cause a substantial amount of lost work and school time, overwhelm hospitals and regional medical care systems, and are thus associated with a large economic burden to health systems and families. Few other infectious diseases have adversely affected the health and economies of global populations as consistently and extensively as influenza.
Vaccination against seasonal influenza viruses is complicated by the capacity of influenza A and B viruses to undergo continual antigenic change in their two major surface antigens ( antigenic drift ), the hemagglutinin (HA) and neuraminidase (NA) proteins. Antigenic drift results from the accumulation of point mutations in the RNA genes encoding HA and NA proteins and leads to the emergence of new variant influenza strains ( Fig. 33.1 ). As the prevalence of antibodies against older variant viruses increases in the population, the circulation of those older, previously dominant variants is suppressed, allowing new antigenic variants to become predominant. When prevalence of antibodies against the new variant virus increases within a population, yet another antigenic variant emerges and the cycle continues. This ongoing process of antigenic drift ensures a continually renewed pool of susceptible hosts and the repetitive occurrence of epidemics. The occurrence of antigenic drift requires robust global surveillance systems that can monitor for the emergence of new strains, and careful review of these data contribute to semiannual updates to influenza vaccine formulations. , The efficacy of annual influenza vaccines is optimal when vaccine viruses are antigenically well matched with circulating viruses. Antigenic match and vaccine efficacy may be reduced in some years and this remains a substantial challenge for global control and prevention efforts.
Finally, the importance of influenza lies also in its capacity to cause global pandemics. Influenza pandemics are the result of antigenic shift , when an influenza A virus with an HA or an HA-NA combination that has never or not recently infected humans gains the ability to infect, cause disease and transmit efficiently among humans ( Fig. 33.1 ). In this case, the population immunity to the new subtype is sufficiently low which facilitates person-to-person transmission and increases severity of illness among those infected. As a result, pandemics are generally associated with higher rates of illness and death compared with epidemics of seasonal influenza. Substantial investments have been made in expanding global surveillance for new emergent influenza viruses, creating more robust pandemic response plans, proactive pandemic vaccine and antiviral development and stockpiling and in forming more coordinated international partnerships. These efforts produced real benefits during the 2009 influenza pandemic response and were built upon for the noninfluenza SARS-CoV-2 pandemic declared by the World Health Organization (WHO) in March, 2020, but there is a recognition that continued work is required for more effective responses to future pandemics.
BACKGROUND
Clinical Presentation
Influenza is characterized by respiratory symptoms, such as cough and sore throat, along with constitutional symptoms, such as fever, headache, myalgias, chills, fatigue, and anorexia. , , In uncomplicated influenza cases, signs and symptoms have abrupt onset and generally persist for approximately 7 days, but resolve with non-specific therapies. The presence of cough and fever are the best predictors of influenza illness in adults and children during periods of influenza circulation. Fever usually ranges between 38°C and 40°C, but may be higher, particularly in children, and usually lasts for 3–5 days. Cough is usually unproductive of sputum. Rhinorrhea and nasal congestion are common, especially in children. Substernal tenderness and photophobia occur less frequently. Gastrointestinal symptoms, such as vomiting, diarrhea and abdominal pain are less common, but more likely to occur in children. Parotitis, usually with fever and sore throat, has been associated with influenza virus infections, especially during influenza A(H3N2) virus predominant seasons. , Rash has occasionally been described with influenza B virus infections. Young infants may present only with unexplained high fever, sepsis-like syndrome, or dehydration without prominent respiratory symptoms. , Influenza can present as febrile seizures in young children. In the elderly, fever may be absent and the presenting signs may include anorexia, lassitude or confusion. Illness typically improves within a week, but cough and malaise may persist for 2 or more weeks. A minority of patients may experience fatigue for months.
Asymptomatic influenza virus infections are likely common and may account for >30% of all influenza, although estimates have varied considerably depending on methods used to confirm influenza and study design. Asymptomatically infected persons can shed detectable influenza virus and may transmit influenza to others.
While any influenza illness can result in severe disease and complications, the risk of complications from influenza is elevated in persons with certain underlying health conditions, young children, and elderly persons. , In addition, pregnant women have been shown to have higher rates of hospitalizations associated with seasonal influenza, especially those with underlying health conditions. In some studies, seasonal influenza virus infection has been associated with increases in some adverse pregnancy outcomes, such as late pregnancy loss and reduction in mean birthweight of term infants. While increased mortality due to seasonal influenza among pregnant women has not been consistently observed, increased complications and risk of death in this population have been documented during pandemics. During the 2009 pandemic, pregnant women accounted for 6-10% of all patients who required hospitalization or died. , , , In addition, risk factors for severe disease highlighted during the 2009 pandemic include morbid obesity and aboriginal ethnic or racial origin (e.g., American Indian, Alaskan Native, First Nation peoples, Australian aboriginal peoples). While risk factors for complications are well known, severe influenza complications and deaths can also occur annually among persons who have no known risk factors. ,
The most common serious complications of influenza include exacerbation of underlying chronic pulmonary and cardiopulmonary diseases, including acute cardiovascular events. , Increased hospitalizations and healthcare visits associated with influenza have been reported among persons with chronic obstructive pulmonary disease, , asthma, , , and congestive heart failure. , Children with underlying neurologic diseases have increased risks of hospitalization and death, likely because of pre-existing difficulties handling respiratory secretions or restrictive lung disease. Exacerbations of diabetes, renal diseases, , and hemoglobinopathies , have also been reported. Persons with severely immunocompromising conditions, including some cancers, hematopoietic and solid organ transplant recipients and AIDS have a higher risk of severe or prolonged disease and chronic viral shedding associated with influenza. , ,
In addition to exacerbations of underlying respiratory conditions, influenza can cause lower respiratory tract disease with primary viral pneumonia or secondary bacterial pneumonia in both adults and children. Influenza has been associated with approximately 10% of patients hospitalized with lower respiratory infections in studies from developed and developing country settings which have been conducted for at least one full year, with higher proportions observed during periods of influenza circulation. , Primary viral pneumonia can range from mild disease with radiographic evidence of pneumonia to severe disease with respiratory failure. Primary viral pneumonia and pneumonitis can occur during any influenza virus infection but is more commonly observed during pandemics, such as in 2009, where severe cases with shock and respiratory failure were reported. , , Primary viral pneumonias are also reported among infections with novel influenza A viruses, such as avian influenza A(H5N1) and A(H7N9). , Influenza cases can lead to pneumonias due to secondary bacterial infection, most commonly associated with Streptococcus pneumonia and Staphylococcus aureus . , , , Bacterial pathogens have been detected in approximately 20–40% of pediatric influenza-associated deaths. ,
More common respiratory tract complications of influenza include otitis media and laryngotracheobronchitis in children and bronchitis in adults. While less common, influenza is associated with nonrespiratory complications that affect almost all other organ systems. , In one U.S. study, hospitalized adults with laboratory-confirmed influenza had pneumonia (36%), sepsis (23%), and acute kidney injury (20%) listed as most common discharge diagnoses. Neurologic complications include febrile seizures in children, encephalitis/encephalopathy (associated with thalamic involvement of the brain), , aseptic meningitis, transverse myelitis and Guillain-Barre syndrome. Reye’s syndrome, an encephalopathy with hepatic inflammation associated with influenza, has been reported primarily in children associated with salicylate ingestion. The incidence of Reye’s syndrome has decreased dramatically in the U.S. after warnings were issued in the 1980s regarding the use of aspirin to treat children. Myocarditis and pericarditis were reported in association with influenza, especially with influenza B virus infections in children. Myositis with rhabdomyolysis and myoglobinuria has been reported with influenza but is uncommon. , Influenza can present as sepsis-like syndromes in infants and has been associated with hematologic abnormalities, including lymphopenia and disseminated intravascular coagulation.
Virology
Taxonomy and Nomenclature
Influenza viruses, together with Thogoto-like viruses, form the family Orthomyxoviridiae . Influenza viruses are divided into four genera, influenza virus A , influenza virus B, influenza virus C , and influenza virus D, based on antigenic differences in two major structural proteins, the nucleoprotein (NP) and the matrix protein (M). Influenza A viruses are further classified into subtypes according to the properties of their membrane glycoproteins, HA and NA ( Fig. 33.1 ). Eighteen HA subtypes and eleven NA subtypes have been identified among influenza A viruses. The nomenclature of human influenza viruses includes the type of isolate, the geographic location where it was isolated, a laboratory identification number, the year of isolation, and for influenza A viruses, the subtype of the HA and NA (e.g., A/Panama/2007/1999 [H3N2]). For animal influenza viruses, the type of animal from which the sample was obtained is also included (e.g., A/chicken/Hong Kong/220/1997 [H5N1]).
Natural Hosts
Influenza A viruses naturally infect humans. Influenza viruses of the A(H1N1) and A(H3N2) subtypes currently circulate among humans while A(H2N2) viruses circulated among humans in the mid-1900s. Among all influenza A HA and NA subtypes isolated to date, 16 HA (H1-16) and 9 NA (N1-9) subtypes have been isolated from wild aquatic birds which serve as a natural reservoir and source of novel genes for pandemic influenza viruses. In contrast, recently identified H17N10 and H18N11 influenza A viruses have been isolated from bats, but neither of these subtypes have been detected in wild birds. Beyond humans, influenza A viruses also infect a wide range of gallinaceous poultry, pigs, horses, dogs and occasionally, sea mammals. The most recent influenza pandemic was caused by a novel influenza A H1N1 virus in 2009 (referred to as A(H1N1)pdm09), which possessed a unique combination of gene segments including genes that originated from swine, avian and human influenza viruses that were established in pigs in North America and Europe ( Fig. 33.2 ). Widespread circulation of the 2009 H1N1 pandemic virus occurred in humans before infections in swine were documented; studies have subsequently shown that humans infected with the A(H1N1)pdm09 virus can infect swine and occasionally, companion animals. Interspecies transmission of influenza A viruses has occurred, as demonstrated by the transmission of influenza A(H5N1), A(H7N9) and A(H9N2) viruses from poultry to humans and can result in severe illness and death. Similarly, multiple subtypes of influenza A viruses from the avian reservoir, including H5 and H7 subtype viruses, have caused illness and death in many different animal species not previously known to be infected with influenza A viruses, such as cats. Although influenza B virus infection of seals, dogs, and other animals has been sporadically documented, humans are the primary host for influenza B viruses. Influenza C viruses infect only humans and pigs and cause sporadic cases or localized outbreaks of mild upper respiratory tract infection. , Influenza D viruses have spread beyond their natural reservoir of cattle to infect pigs, with only limited serologic evidence to support human infection to date. ,
Virus Structure
Influenza viruses are enveloped and contain segmented RNA-negative sense genomes ( Fig. 33.3 ). Segmentation of the viral RNA allows exchange of genes (i.e., genetic reassortment) among influenza viruses of the same type. The segmented RNA genome is associated with NP and three viral polymerase proteins (PB1, PB2, and PA) within helical nucleocapsids that are surrounded by the matrix protein and the virus envelope derived from the host cell membrane. The spherical, often pleomorphic 80–120 nm virus particles have a surface layer of spike-like projections, 10–14 nm long, consisting of HA and NA proteins.
HA is the major antigen against which the host’s protective antibody response is directed and is responsible for attachment of influenza viruses to oligosaccharide-containing terminal sialic acids on the cell surface during early stages of infection ( Fig. 33.4 ). HA of avian influenza viruses preferentially bind sialic acid (SA) residues attached by an α2,3 linkage to galactose (α2,3Gal) while human viruses bind predominantly to those bearing α2,6Gal; swine viruses tend to bind both α2,3Gal and α2,6Gal providing the molecular basis for the observations that pigs serve as a mixing vessel for both avian and human viruses thus facilitating the generation of new influenza viruses. However, differences in structural topology between sialylated glycans, and recognition of N-acetyl or N-glycolyl neuraminic acid by influenza A viruses, represent additional potential determinants of host range beyond the sialic acid linkage itself. , Additionally, the distribution of SA residues in the respiratory tract varies among birds, humans and pigs. While SA α2,6Gal is expressed predominantly in the trachea in humans, α2,3Gal is expressed on nonciliated cuboidal cells in the region between the bronchioles and alveoli as well as on alveolar cells, contributing to why humans are infected sporadically with avian influenza viruses. , Furthermore, the distribution of α2,3Gal SA in the lower respiratory tract of humans limits human-to-human transmission of avian influenza viruses via aerosols.
Beyond differences in receptor specificity, the presence of multiple basic amino acids (or other sequence insertions) at the cleavage site in some avian H5 and H7 HAs and subsequent cleavage by the endoprotease furin is attributed to enhanced pathogenicity in susceptible species. , Since furin is widely distributed in the body in various tissues and organ systems, avian influenza viruses containing polybasic amino acids are able to infect a wide range of cell types leading to severe disease. The HA is a homotrimeric transmembrane protein consisting of a globular head (HA1) and membrane anchoring α-helical chain stalk region (HA2). The error-prone nature of RNA polymerase coupled with immune selection pressure leads to hypervariability in the globular head region. Phylogenetic differences of the HA led to grouping influenza A viruses into Group 1 or 2. H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17 and H18 HAs are placed in group 1, and H3, H4, H7, H10, H14, and H15 are placed in group 2. While the immunodominant immune response consists of strain-specific antibodies directed against the globular head (HA1), broadly neutralizing antibodies directed to the highly conserved conformational stalk (HA2) region can be induced. These broadly neutralizing antibodies have been shown to neutralize many strains within the Group 1 or Group 2 influenza A viruses. ,
NA is less abundant on the viral surface relative to HA and facilitates release of mature virus from infected cells. It is a homotetrameric protein with a mushroom head and is anchored with a short stem. Similar to HA, NA types of influenza viruses from the avian reservoir are separated into two groups. Group 1 contains the N1, N4, N5 and N8 subtypes, and group 2 consists of N2, N3, N6, N7, and N9 subtypes. However, N10 and N11 subtypes isolated from bats exhibit several phylogenetic and functional differences and do not belong to either group. , Antibody to NA is believed to restrict virus spread and reduce illness severity. By definition, the HA and NA of different subtypes are serologically distinct. While some serological cross-reactivity may exist among HA or NA of the same influenza subtype but from different species, the extent of cross-protection afforded by such responses is not well understood.
The influenza A virus envelope also contains matrix (M1) and transmembrane (M2) proteins. M1 protein is located inside the viral membrane and is thought to add rigidity to the lipid bilayer, whereas the M2 protein functions as a pH-activated ion channel. Recent studies support a role for the influenza M segment in both species host restriction and virus transmission potential. A nonstructural gene encodes two proteins: the multifunctional NS1 which is found only in virus-infected cells and nuclear export protein (NEP), also known as NS2, which is a minor virion component involved in nuclear export of the nucleocapsids containing viral RNA.
Pathogenesis as It Relates to Prevention
Infection and viral replication of seasonal influenza viruses occur primarily in the columnar epithelial cells of the respiratory tract, , but viral replication can occur throughout the respiratory tract. After infection, epithelial cells become vacuolated, lose cilia, and become necrotic. Regeneration of epithelium takes approximately 3–4 weeks, during which time pulmonary abnormalities can persist. Influenza viruses are rarely isolated outside of the respiratory tract, even though infection can result in signs and symptoms referent to several other organ systems and is associated with pronounced constitutional manifestations. While possible among severe cases, viremia is rarely observed with seasonal influenza virus infections, although it has been detected at higher frequency in human infections with avian influenza A(H5N1) viruses.
In humans, influenza viruses are spread by exposure of susceptible mucosal surfaces to respiratory secretions containing virus from an infected person. Inhalation of virus-containing aerosols represents a primary means of exposure resulting in productive infection; the ocular surface represents a secondary mucosal surface also permissive to influenza virus infection. The most likely modes of transmission are through large or small droplet aerosols produced by expiratory activities of infectious individuals, inclusive of breathing, talking, coughing, and sneezing. , The relative contribution of large droplet versus aerosol transmission is not fully understood, but influenza viruses have been detected in large and small droplets, and recent data indicate that aerosol transmission of fine droplets represents a significant source of transmission. , Influenza virus viability in aerosols can be modulated by environmental parameters, including temperature and humidity. Transmission of virus by direct and/or indirect contact with infected respiratory secretions can also occur, including transmission through contaminated fomites. No evidence for transmission through bloodborne or sexual routes has been described.
The incubation period for influenza is commonly 2 days, but ranges from 1 to 4 days. Virus can be detected in the upper airway for up to a day before symptoms and approximately 3–5 days after illness onset in adults. The peak of viral shedding, 1–3 days following illness onset, likely coincides with the period during which most transmission occurs; viral shedding typically follows clinical symptomology and virus levels are undetectable within 6–7 days of illness onset. Children may shed virus for up to 2 weeks, and have higher virus titers in their upper airway, , which is one factor that promotes transmission in school settings. Severely immunocompromised persons can shed virus for months.
The transmissibility or the reproductive number (Ro) for influenza has been estimated to be approximately 1.5–2, and the serial interval (the interval between the onset of symptoms in a case patient and the onset of symptoms in the contacts who were infected by that patient) is usually estimated to be 2–3 days. However, given the typical short incubation period for influenza, influenza outbreaks may be explosive, especially in highly susceptible populations as can occur in a pandemic. , , In recent years, mathematical modeling has further improved our understanding of global burdens and transmission dynamics of influenza viruses during both epidemic and pandemic events. ,
Diagnosis
Commonly used diagnostic tests to detect influenza viruses include rapid antigen assays, reverse-transcriptase polymerase chain reaction (RT-PCR), and rapid molecular assays. Radioimmunoassays, fluoroimmunoassays, and enzyme immunoassays which detect viral antigen in clinical samples, and viral culture are now rarely used for diagnosis due to lower sensitivity compared with RT-PCR and the need for specialized equipment. ,
Diagnostic testing for influenza may be for surveillance or for informing clinical management, such as antiviral or antibiotic treatment, infection control or additional diagnostic testing. In the United States, if a novel influenza A virus infection is suspected, such as human infection with an avian or swine influenza virus, molecular assays available at state and local public health laboratories or CDC are recommended. ,
Rapid antigen tests can provide results within 10–15 minutes and function as “point of care” tests for rapid diagnosis of influenza. Differentiation of influenza A and B viruses vary based on test. These tests generally have a sensitivity of 42–60% and a specificity of >98% for influenza A and B viruses, with sensitivity estimates in the higher range derived from reports from manufacturers. , In 2017, the U.S. Food and Drug Administration (FDA) reclassified rapid influenza diagnostic tests to class II devices with new minimum published requirements of assay sensitivity of at least 80%. , During periods of low influenza circulation, false positive results from rapid influenza diagnostic tests are more common than detection of actual influenza infection.
Influenza virus nucleic acid can be detected through RT-PCR or other molecular assays. These assays are now commonly used to diagnose influenza virus infections and have supplanted virus culture as the “gold standard” for virus detection due to their high sensitivity and specificity. , Some molecular assays can produce results within 15–30 minutes and are considered “point of care” tests. While most molecular assays can discriminate between influenza A and B viruses, some can identify specific influenza A subtypes. Molecular multiplex assays can distinguish influenza virus from other respiratory pathogens. Recent assays can detect both SARS-CoV-2 and influenza A and B viruses.
Isolation of influenza viruses in cell culture or eggs followed by hemagglutination-inhibition (HI) testing to identify the virus was previously the “gold standard” for influenza diagnosis but has been largely replaced by RT-PCR. Isolation of influenza viruses remains critical for characterizing and identifying viruses for use in influenza vaccines. The sensitivity of viral culture depends on when in the course of illness the specimen is collected and its quality. Results usually are not available for at least 3 days, although some rapid culture methods allows virus to be detected within 18–24 hours.
Prior influenza virus infections can also be detected by measuring increases in influenza-specific antibody between acute and convalescent serum samples. Techniques for measuring antibody against influenza in sera include HI, virus neutralization, enzyme immunoassay, and complement fixation. In general, these tests are little used outside of a research setting and may underestimate infections among recently vaccinated individuals.
Influenza virus genome sequencing has been used as a research and public health tool to genetically characterize influenza viruses, identifying antigenic drift and shift events and markers of antiviral drug resistance. Next-generation sequencing, also referred to as whole genome sequencing or deep sequencing, has expanded upon the information obtained by older sequencing techniques, such as Sanger sequencing. Next-generation sequencing provides genetic data on the entire virus genome, can differentiate between multiple viruses in a single specimen, and facilitates comparison of viruses for surveillance, vaccine strain selection and vaccine development activities. As sequencing capacities expand and time to analyze data and report results decreases, the uses of next generation sequencing for diagnosis will expand and could be more useful in some clinical situations.
Drugs Active Against Influenza Viruses
Three classes of prescription medications have been approved in the U.S. and elsewhere for use against influenza virus infections: adamantanes, NA inhibitors, and polymerase inhibitors. The adamantane derivatives, amantadine hydrochloride and rimantadine hydrochloride, inhibit viral replication by blocking the proton channel formed by the M2 protein of influenza A viruses. The channel activity is necessary for viral particle uncoating during early and late stages of viral replication. A single substitution at one of five residues (26,27,30,31,34) of the M2 protein has been associated with resistance to all adamantane derivatives. , Widespread emergence and now predominance of adamantine resistance among human influenza A(H3N2) and A(H1N1) viruses and among animal influenza A viruses have severely limited the usefulness of these medications for influenza treatment or prophylaxis, with only limited detection of viruses sensitive to these antiviral medications among currently circulating viruses.
The NA inhibitors (NAI), zanamivir, oseltamivir, peramivir, and laninamivir inhibit the NA of both influenza A and B viruses. Blocking the active site of the NA results in viral aggregation at the host cell surfaces and fewer viruses released from infected cells. , Resistance to NAI can occur from substitutions in the active site of the NA or its proximity that reduce drug binding affinity. , Cross resistance to multiple NAI can occur with single residue substitutions, often with varying degrees of resistance. , In addition, multiple amino acid substitutions in the NA that result in resistance to multiple NAI have been reported. , In 2008, widespread and unexpected circulation of seasonal influenza A(H1N1) viruses that were resistant to oseltamivir and peramivir due to NA substitution H275Y occurred; however, susceptibility to zanamivir was maintained. In 2009, the H275Y-containing seasonal A(H1N1) viruses were replaced by influenza A(H1N1)pdm09 viruses that were susceptible to all NAI. , Rates of oseltamivir resistance among seasonal influenza viruses are generally low, and are more frequently detected among circulating A(H1N1) viruses compared with A(H3N2) viruses; NA inhibitor resistance is also low among circulating influenza B viruses. Detection of viruses with reduced susceptibility to NAI among animal influenza viruses such as A(H5N1) is documented but generally uncommon. Influenza viruses with NA inhibitor resistance have emerged both during antiviral treatment (notably among immunocompromised individuals) and in the absence of antiviral treatment (implying exposure to a virus already bearing a resistant phenotype or the spontaneous acquisition of a resistant phenotype during infection), underscoring the need for continued monitoring of circulating viruses bearing reduced susceptibility to these compounds. , , , ,
The polymerase inhibitor baloxavir marboxil, first approved for use in the U.S. and Japan in 2018, targets the cap-dependent endonuclease of both influenza A and B viruses. By targeting the influenza virus polymerase, this antiviral blocks the transcription of new viral mRNA. Among cases of uncomplicated influenza, baloxavir administration has been shown to reduce viral loads in upper respiratory tract specimens within one day after treatment, and has demonstrated postexposure prophylactic efficacy in reducing virus spread to household contacts. , Rates of baloxavir resistance among circulating influenza A viruses remain low. , However, emergence of viruses with reduced baloxavir susceptibility has been reported in clinical trials, especially among individuals with prolonged viral shedding or illness. , The most frequent amino acid change associated with reduced baloxavir susceptibility is I38T in the polymerase acidic protein (PA), though other variants at position 38 have also been reported. Laboratory studies support baloxavir efficacy against animal influenza viruses (including H5, H7, and H9 subtypes).
EPIDEMIOLOGY
Seasonality
Influenza occurs in seasonal peaks in much of the world. In temperate climates, influenza activity typically occurs during the late autumn and winter months of northern hemisphere (October-April) and southern hemisphere countries (May-September). In tropical climates, while influenza transmission occurs year-round, one or two annual peaks can often be discerned in many countries. In large countries, differences in seasonal occurrence of influenza can be observed within the country. , Despite a vaccine nomenclature indicating “southern” and “northern” hemisphere formulations, as data from subtropical and tropical countries accumulate, it is clear that seasonal peaks of influenza do not fall neatly into two seasonal patterns. , , Data demonstrating a summertime peak in influenza in Central American and southeast Asian countries resulted in several countries changing vaccine recommendations to use the southern hemisphere formulation, despite residing in the northern hemisphere. ,
Sporadic cases and institutional outbreaks can occur at any time of the year, including the summer months. Outbreaks associated with large groups of international travellers suggest that large outbreaks of influenza may begin to occur more frequently during unusual times of the year. , Within communities, epidemics or outbreaks typically last 6–8 weeks or longer. Reasons for the seasonality of influenza are not completely understood and are likely multifactorial and include the role of temperature and humidity on virus survival and seasonal differences in behavior (e.g., indoor crowding in winter months and school attendance).
Even in locations where seasonal peaks occur each year, the start, peak, duration, and size of individual seasons vary substantially from year to year and are not predictable. In the U.S., most seasons peak between December and March. The timing, size, and impact of epidemics reflect the interplay of several factors, including the extent of the virus’ antigenic variation, virulence, and transmissibility; the extent of immunity in the population; and the specific population groups that are affected. During the COVID-19 pandemic, seasonal influenza activity was dramatically reduced globally likely due to global reductions in travel, social distancing and masking measures and school closures, but virus interference may also have played a role.
Incidence of Disease
Influenza attack rates vary by season, by geographic location, by setting (e.g., institutional, closed settings versus community settings), by predominant subtype/type and by age group. In addition, reported attack rates may vary considerably depending on diagnostic methods. Not all persons with infections documented by RT-PCR or culture will have documented seroconversion and vice versa. However, approximately 30–50% of persons with serologic evidence of infection after an influenza season (including during the 2009 H1N1 pandemic) are either asymptomatically infected or have very mild illness. , , , ,
Among community studies, families in Seattle had annual attack rates of 19% and 20%, respectively, for serologically confirmed influenza A and B infections between 1965 and 1969. In the same study population during 1978–1979, rates of influenza A(H1N1) virus infection soon after its re-emergence in 1977 were about 31% among persons born after 1956. In Michigan, a community study during 1966–1971 found infection rates of 17% and 8% using serology for influenza A and B virus infections, respectively, but rates of only 1.4% and 1.5%, respectively, using virus isolation. The attack rates by age group, based on serology for influenza A, were about 15–24% in children younger than 5 years, about 17–21% in children 5–19 years and about 12–18% in persons older than 19 years. Rates were lower for influenza B virus infections. In Houston, between 1976 and 1984, estimated attack rates ranged from 36 to 45% in children 5 years and younger, from 40 to 48% in children 6–17 years and from 21 to 23% in persons 18 years and older. In household cohorts in Hong Kong (2010–2012) and Nicaragua (2012–2014), annual attack rates for influenza varied between 7% and 31%. ,
During the 2009 H1N1 pandemic, the attack rate, as measured by four-fold increases in specific antibody titer among other household members after laboratory confirmation of an index household member, was 20%; 13% of contacts were shown to have viral shedding by RT-PCR. Serial cross-sectional seroprevalence data obtained before and after the summer-fall 2009 H1N1 pandemic wave in the U.S. indicated that the overall attack rate was 11%, including 43% in persons aged 5–14 years, 16% in persons aged 15–19 years, 12% in persons aged 20–29 years, and 5% in persons aged 30–59 years. Attack rates among institutionalized populations can be much higher. In military and boarding school populations, attack rates up to 87% and 90%, respectively, have been reported. One review of outbreaks in nursing home populations estimated an average attack rate of 43%, although higher rates have also been found. Influenza outbreaks also have been described in hospitals and aboard cruise ships. ,
Pandemics of Influenza
Pandemics of influenza A viruses have occurred unpredictably and relatively infrequently; in 1918 (when a new H1N1 emerged), and again in 1957 (H2N2), 1968 (H3N2), and 2009 (H1N1). , Influenza viruses that have not circulated in humans in recent years are considered “novel” and arise through antigenic shift or through direct transmission of a novel influenza A virus into the human population from animals. Influenza B viruses do not pose a pandemic threat because humans are the primary host making reassortment with novel animal viruses unlikely. Antigenic shift among influenza A viruses can occur in at least two ways. In the first mechanism for shift, the simultaneous infection of a host by influenza A viruses of two different subtypes allows corresponding viral genes to be exchanged (or to reassort) between the infecting viruses. For example, infection of a pig simultaneously by both an avian influenza A virus and a human influenza A virus can allow genes from the virus normally in circulation among birds to reassort with genes of the influenza A viruses circulating among humans. The resulting “reassortment” of human and avian influenza genes could produce new influenza viruses containing many different combinations of genes including those containing novel HA or HA-NA genes from the avian influenza viruses. The viruses that caused the 1957, 1968, and 2009 pandemics all showed evidence of genetic reassortment between avian and human influenza viruses. ,
The second mechanism involves direct transmission of avian viruses to humans with subsequent adaptation to the new host. The 1918 pandemic influenza virus is thought to have arisen in this way. Fears of pandemic influenza have arisen due to the emergence of avian viruses, such as A(H5N1) and A(H7N9) viruses, which have demonstrated the ability to infect and cause severe disease in humans. Since the emergence of highly pathogenic avian influenza A(H5N1) in 1997 in Hong Kong, more than 850 human infections have been documented, with a case fatality rate of approximately 53%. , , , Similarly, avian influenza A(H7N9) viruses emerged in China in 2013 and continued to infect humans until 2018, infecting more than 1560 persons, almost all in China, of whom approximately 39% died. , Swine-origin influenza A viruses have also been occasional causes of illness in humans in the U.S. and elsewhere, mostly resulting in mild respiratory illnesses. Aside from occasional human-to-human spread of these avian and swine-origin viruses, almost all human infections have been by direct transmission from infected poultry or swine to humans ; none of these viruses have as yet demonstrated the capacity for sustained human-to-human spread. However, the viruses are geographically widespread in poultry and swine populations, with recent H5 subtype viruses identified in poultry in the U.S.
Pandemics are of great public health significance because of their capacity to result in substantial mortality and morbidity. In addition, because pandemics spread quickly, affect entire countries and regions in a short time, and may have more than one wave, they have the capacity to cause disruptions in healthcare delivery and other societal functions. Between the spring of 1918 and the spring of 1919, three waves of illness caused by influenza A(H1N1) viruses swept around the world leading to more than 550,000 deaths in the U.S. and more that 20 million deaths worldwide. Three subsequent influenza pandemics, beginning in 1957, in 1968, and in 2009 were associated with the emergence of the influenza A(H2N2) virus, the influenza A(H3N2) virus, and a new A(H1N1) virus, respectively, but resulted in lower mortality rates compared with the 1918 pandemic. In fact, the most recent pandemic, which was characterized by relatively low attack rates among persons older than 60 years, is estimated to have resulted in fewer deaths than many annual seasonal epidemics in the U.S. This likely reflects lower susceptibility to A(H1N1)pdm09 virus infection due to prior infection with 1918-like viruses that circulated until the 1940s. During influenza pandemics, severe infections were much more common in children and younger adults compared with typical winter influenza seasons, in which >90% of deaths and approximately 60% of hospitalizations occur among persons aged 65 years or older. During 2009, the first year after the emergence of the virus, an estimated 61 million illnesses, 274,000 hospitalizations, and 12,400 deaths associated with the A(H1N1)pdm09 virus occurred in the United States. During this period, the highest estimated attack rates occurred in children and young adults, the highest estimated hospitalization rates occurred in children less than 5 years of age, and 90% of estimated deaths occurred in persons less than 65 years of age. In one estimate, the mean age among persons whose deaths were attributed to the 2009 H1N1 influenza pandemic was 37 years, compared with a mean age of 76 years among deaths attributed to seasonal influenza A(H3N2) viruses.
Because of the potential for the development of a new influenza pandemic virus with higher case-fatality rates, preparedness planning has been a priority for most countries since the emergence of A(H5N1) avian viruses and associated human infections in 1997. Critical to preparedness has been planning for the development of monovalent pandemic vaccines, hoping to circumvent the problem that pandemic vaccines may be available only after the pandemic has begun, mitigating their effectiveness. These plans were effective in responding to the 2009 H1N1 pandemic, and while vaccine was delivered relatively late compared with virus circulation, it was demonstrated to be effective. , Efforts are underway to speed the process for pandemic vaccine development and delivery, including the continual updating of candidate vaccine virus strains and work toward more broadly reactive vaccines that might increase the value of prepandemic stockpiled vaccines.
Significance as a Public Health Problem
Influenza is a significant public health threat because of relatively high annual attack rates, coupled with the capacity to cause large numbers of severe illnesses requiring medical care. During influenza seasons, an estimated 5–15% of the population in the United States can develop influenza, , , but attack rates of 40–50% within institutions such as nursing homes are not unusual. , In communities, influenza cases often appear first among school-age children, among whom attack rates usually are the highest. , , , While attack rates among the elderly are generally lower due to differences in mixing patterns and preexisting immunity, rates of serious disease during most seasonal influenza epidemics are highest among the elderly, the very young, and those with certain underlying chronic conditions. Influenza epidemics are generally associated with increases in physician visits, hospitalizations, and deaths, as well as increases in school and workplace absenteeism. The WHO has estimated that between 291,243 and 645,832 deaths occur globally each year as a result of influenza. The large numbers of medical care visits generated by influenza can overwhelm medical care systems, requiring hospitals and emergency services to divert patients. As a result, substantial medical care and societal costs are incurred each season.
Influenza-associated severe disease cases (such as those leading to hospitalization or death) are usually not confirmed using influenza-specific laboratory tests because of low testing rates or because a person presents for care late in the course of illness, when testing may be less sensitive. As a result, influenza-associated mortality and hospitalizations are usually estimated using models.
During 2010–2011 through 2019–2020 in the U.S., 9 million–45 million illnesses, 140,000–810,000 hospitalizations, and 12,000–61,000 deaths were estimated to occur annually. , , The estimated annual number of deaths related to influenza, and the estimation of severity, is typically higher in years where influenza A(H3N2) viruses predominate. , ,
PASSIVE IMMUNIZATION
Passive immunization consists of transfer of antibodies in serum or laboratory-made monoclonal antibodies from an immunized or infected and recovered individual to a naïve individual to protect and/or treat the disease temporarily. During the 19th century, either hyperimmune or convalescent homologous or heterologous polyclonal sera was successfully used for prophylactic and therapeutic treatment against several infectious diseases, namely rabies, tetanus, diphtheria, and influenza before the advent of antibiotics and antivirals. During the 1918 influenza pandemic, administration of convalescent human serum reduced the absolute risk for death, with a pooled risk difference between treated and untreated patients of 21% (95% CI: 15–25) if administered within 4 days of the onset of symptoms. However, delayed treatment had a reduced effect on favorable outcomes. After the identification of the causative agent of influenza, Francis and Magill in their landmark study demonstrated that transfer of sera from either influenza virus-infected ferrets and mice or virus-immunized rabbits into naïve mice protected them against homologous viral challenge, thus setting the stage for a series of animal studies as well as medical intervention strategies against epidemic influenza. In addition, passive immunization of sera in patients diagnosed with influenza reduced not only the severity but also the duration of disease. Despite the demonstrated clinical utility of passive immunization for prophylaxis and treatment against influenza from earlier studies, this approach did not receive much attention due to safety issues associated with the use of human convalescent sera and hyperimmune sera generated in heterologous species. However, an impending avian influenza pandemic and technological advances in generating monoclonal antibodies and polyclonal sera using a variety of approaches, along with improved knowledge of the structural details of the hemagglutinin, reinvigorated interest in exploring passive immunization strategies against pandemic, and epidemic influenza. A recent case report demonstrated the clinical utility of passive immunization by administrating convalescent plasma from a patient recovered from A(H5N1) virus infection to a A(H5N1) virus-infected individual, which resulted in a 10-fold reduction in viral load within the first 8 hours of administration and undetectable levels of virus within 32 hours, leading to the patient’s recovery. However, in a phase 3 clinical study no clinical benefit was observed in 92 patients who received high-titered (≥80) influenza plasma when compared with 48 patients who received low-titered plasma. Administration of human or humanized monoclonal antibodies (mAbs) with specificities against the receptor binding domain or stalk region of the HA or polyclonal sera against HA or the conserved extracellular domain of M2 (M2e) with or without antiviral agents protected animals against lethal challenge and reduced viral replication. Antibodies varied in their ability to confer protection when given 24–72 hours prior to and up to 72 hours postchallenge. Intranasal administration was more effective and dose sparing compared with parenteral routes. Furthermore, a cocktail of mAbs was superior and prevented the generation of escape mutants compared with use of individual mAbs alone. Antibodies against the highly conserved stalk region of the HA protein have been shown to be broadly neutralizing both within and across HA subtypes, by inhibiting viral fusion and through the lysis of virus-infected cells by Fcγ receptor-expressing immune cells, a mechanism known as antibody dependent cell-mediated cytotoxicity (ADCC). In contrast, antibodies that target the globular head domain of the HA have narrow specificity and do not support ADCC by Fcγ receptor+ cells. , Several mAbs with specificities against the conserved stalk region of HA are currently in phase 1/2 clinical studies. In a recent human challenge study, healthy adult participants between the ages of 18 and 45 years were inoculated intranasally with 10 6 TCID 50 of A/California/07/2009 (H1N1) influenza virus and received a human mAb, VIS410 which targets the stalk region of Group 1 and Group 2 influenza A viruses. In the first part of this study, 13 subjects received a placebo and 18 subjects received 2300 mg of a single dose of VIS410 while subsequent evaluation within the same study looked at safety of the administration of a higher mAb dose without a placebo group. VIS410 treatment reduced the mean viral load by 76%, as estimated by quantitative RT-PCR and 91% as determined by TCID50 assays when compared with placebo. However, the treatment was associated with gastrointestinal symptoms with a corresponding transient elevation of IL-8 and TNF-α. Influenza symptoms were mild to moderate with faster resolution in the VIS410 group. The production costs of mAbs and their shorter duration of protection limits their use to critically ill patients and individuals with underlying medical conditions. Genetic immunization and vector-based delivery of mAbs against influenza may overcome cost and production constraints and are in preclinical investigations.
ACTIVE IMMUNIZATION
All vaccines mentioned in this chapter are vaccines produced from influenza viruses grown in eggs or mammalian cell culture and subsequently inactivated, or vaccine that contains HA protein produced through recombinant technology that does not require inactivation. ( Table 33.1 ). Live attenuated (cold-adapted) influenza vaccines are described in detail in Chapter 34.
TABLE 33.1
Influenza Vaccines Available in the United States, 2021–2022 Influenza Season (Modified from Grohskopf et al ) *
| Trade Name | Manufacturer | Presentation | Age Indications | Route | HA Antigen/Dose Per Virus (μg) | ||
|---|---|---|---|---|---|---|---|
| Inactivated influenza vaccines, quadrivalent (IIV4), egg-based | |||||||
| Afluria Quadrivalent | Seqirus | 0.5 mL SD PFS | ≥3 years | IM | 15 | ||
| 5.0 mL MDV | ≥6 months e via needle; 18 through 64 years via jet injector | IM | 15 | ||||
| Fluad Quadrivalent (MF59-adjuvanted) | Seqirus | 0.5 mL SD PFS | ≥65 years | IM | 15 | ||
| Fluarix Quadrivalent | GlaxoSmithKline | 0.5 mL SD PFS | ≥6 months | IM | 15 | ||
| FluLaval Quadrivalent | ID Biomedical Corp. of Quebec (distributed by GlaxoSmithKline) | 0.5 mL SD PFS | ≥6 months | IM | 15 | ||
| Fluzone Quadrivalent | Sanofi Pasteur | 0.5 mL SD PFS | ≥6 months † | IM | 15 | ||
| 0.5 mL SDV | ≥6 months † | IM | 15 | ||||
| 5.0 mL MDV | ≥6 months † | IM | 15 | ||||
| Fluzone High-Dose Quadrivalent | Sanofi Pasteur | 0.7 mL SD PFS | ≥65 years | IM | 60 | ||
| Inactivated influenza vaccine, quadrivalent (IIV4), cell culture-based | |||||||
| Flucelvax Quadrivalent | Seqirus | 0.5 mL SD PFS | ≥6 months ¶ | IM | 15 | ||
| 5.0 mL MDV | ≥6 months ¶ | IM | 15 | ||||
| Recombinant influenza vaccine, quadrivalent (RIV4) | |||||||
| Flublok quadrivalent | Sanofi Pasteur | 0.5 mL SD PFS | ≥18 years | IM | 45 | ||
| Live-attenuated influenza vaccine, quadrivalent (LAIV4), egg-based | |||||||
| FluMist Quadrivalent | MedImmune | 0.2 mL single dose prefilled intranasal sprayer | 2 through 49 years | NAS | § | ||
IIV4, quadrivalent inactivated influenza vaccine; IIV3, trivalent inactivated influenza vaccine; IM, intramuscular; LAIV4, quadrivalent live attenuatedinfluenza vaccine; MDV, multi-dose vial; NAS, intranasal; RIV4, quadrivalent recombinant vaccine; SD PFS, single-dose prefilled syringe; SDV, single dose vial.
* Updated tables of U.S.-licensed influenza vaccines expected to be available during the current influenza season may be found in the most recent Advisory Committee on Practices (ACIP) influenza statement, available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html .Clinicians should consult current FDA-approved manufacturer prescribing information for authoritative information concerning dosages, age indications, warnings, contraindications, and precautions for the use of influenza vaccines.
† Per package insert, dose volume for children ages 6 through 35 months is either 0.25 mL or 0.5 mL.
¶ Approved for ages ≥4 years at start of 2020–21 season; approved in March 2021 for ages ≥2 years; and subsequently in October 2021 for ages ≥6 months.
§ Contains 10 6.5 –10 7.5 fluorescent focus units per virus per dose. e For Afluria Quadrivalent, the dose volume is 0.25 mL for children ages 6 through 35 months and 0.5 mL for persons ages ≥3 years.
History of Vaccine Development and Current Inactivated and Recombinant Vaccines
Inactivated Influenza Vaccines
Efforts to develop influenza virus vaccines began soon after influenza A and B viruses were recognized as the etiologic agents of clinical influenza. , The first commercial vaccines were approved for use in the United States in 1945, based on efficacy studies performed in military recruits and college students using inactivated whole-virus influenza vaccines. , An influenza vaccine was of particular interest to the U.S. military during World War II, in part because of the devastation caused in both military and civilian populations by the 1918–1919 influenza pandemic during the late stages of World War I. The ability to grow large quantities of influenza viruses in eggs, elucidation of the physical properties of the viruses, and development of the principles of chemical inactivation made it possible to prepare millions of vaccine doses. ,
The processes used to make the current commercially available inactivated influenza virus vaccines share certain key features including: selecting candidate vaccine viruses, propagating (i.e., growing) vaccine viruses, inactivating and purifying bulk vaccine virus stocks, and combining to formulate multivalent bulk vaccines. WHO and various national authorities select candidate vaccine viruses semiannually, for the northern and southern hemisphere vaccines, respectively. This is done based primarily on the genetic and antigenic characteristics of their HAs. , For preparation of the monovalent intermediate bulk vaccine virus stocks, the selected vaccine viruses are propagated in either eggs or cell culture. Influenza viruses harvested from eggs or cell culture are inactivated and purified to reduce nonviral proteins and other materials introduced during the manufacturing process. These monovalent vaccines are combined to formulate the final multivalent bulk vaccines, which then are filled into containers (such as prefilled syringes and single- or multidose vials).
Improvements in three areas have increased vaccine production. First, the development of ‘high-growth’ influenza A viruses suited to maximal replication in eggs facilitated propagation of candidate vaccine egg-derived viruses. Since the early 1970s, influenza virus A/Puerto Rico/8/1934 (PR8), a strain very well adapted to replication in eggs, has been used to develop influenza A virus reassortants that combine the HA and NA from wild-type viruses with the high growth properties of the PR8 donor virus. , Influenza A virus reassortants derived from PR8 often are more uniformly spherical than wild-type viruses, which may facilitate recovery of virus during the various process steps. The growth characteristics of reassortants vary because the HA and NA also affect the adaptation and replication capabilities of the viruses in growth substrates. The overall advantage provided by strains that replicate well in eggs has meant that most, if not all, influenza vaccines prepared in eggs over the last 35 years have been prepared using a “high-growth” influenza A virus reassortant. An area of continuing investigation is development of reliable high-growth donor strains of influenza B viruses suited to vaccine production.
Second, since the development of cell culture-based influenza vaccines (produced in cell lines such as Madin-Darby Canine Kidney [MDCK] or Vero), both egg-derived and cell culture-derived candidate vaccine viruses may be specified for use in the manufacture of commercially available vaccines each season. Historically, candidate influenza vaccine viruses were initially derived and propagated in the allantoic cavities of embryonated hens’ eggs. Interest in producing vaccines in mammalian cell systems has arisen (1) out of concern that the availability of eggs could be reduced by an event such as an outbreak of avian influenza or Newcastle disease virus that could limit the availability of eggs due to disease in egg-producing hens, (2) because the HAs of viruses grown in eggs frequently exhibit egg adaptive genetic changes that may result in undesirable antigenic alterations in vaccine viruses. Among the inactivated influenza vaccines, most are manufactured using embryonated eggs but mammalian cell culture vaccines are available in the U.S., Europe, and Australia. Development of vaccines produced in cell culture has been promoted in part for pandemic preparedness, both as a tool to meet increased vaccine demand during a pandemic and as a hedge against the possibility that a pandemic strain derived from avian viruses might endanger birds used to produce the eggs for vaccine production.
Third, historically used inactivated influenza vaccines contained whole viruses, and were crude preparations compared with currently available vaccines. The purity of influenza virus vaccines has steadily increased, aided by the introduction of centrifugation and chromatographic steps to reduce residual egg materials. These vaccines retain the immunogenic properties of the viral proteins but are generally associated with reduced reactogenicity, particularly among children. , Since dissolution of the lipid envelope allows retention of immunogenicity with reduction in reactogenicity, “splitting” influenza viruses to produce subvirion preparations has become routine. An intact viral membrane is essential for infectivity of enveloped viruses. Therefore, disruption of the viral envelope adds assurance of viral inactivation. Subvirion vaccines are prepared by using a solvent (such as ether or a detergent) to dissolve or disrupt the viral lipid envelope. Additional purification steps can be taken to reduce the amounts of viral proteins (predominantly influenza M protein and NP), resulting in vaccines referred to as subunit or purified surface antigen preparations.
Recombinant Influenza Vaccines
In addition to inactivated influenza vaccines, recombinant influenza vaccines have been developed, which are produced by introducing the genetic sequence of the HA protein derived from mammalian cell-grown prototype viruses into a continuous insect cell line using a baculorvirus vector. , One such vaccine is currently available in the U.S., which was initially approved as a trivalent version in 2013 and is now available as a quadrivalent formulation. This vaccine is produced without the use of intact influenza viruses and contains purified HA antigen, without other influenza viral proteins. , Moreover, like cell culture-based vaccines, recombinant vaccines, which are produced in insect cells and based on HA gene sequences derived from mammalian cell-grown prototype viruses, do not possess amino acid changes in the HA that result from adaptation of human influenza virus to growth in eggs. Although inactivated influenza vaccines contain other viral proteins such as NA, M, and NP, their levels are not specifically quantified. HA is the only immunogen in the recombinant HA vaccine.
Monovalent Vaccines
While multivalent vaccines are used globally in seasonal immunization programs, monovalent influenza vaccines have been used for responding to specific influenza threats. Most notably, monovalent vaccines were prepared and used for each of the recent pandemics, including the 2009 H1N1 pandemic. , Antibodies to contemporary seasonal influenza A(H1N1) viruses at that time engendered by previous infection or vaccination offered little or no cross-protection against 2009 pandemic H1N1 viruses. As a result, a monovalent vaccine based on one of the original isolates of the virus was produced, and found to be effective in preventing disease associated with the virus, while vaccination with the multivalent vaccine produced using the seasonal A(H1N1) strain was found to confer no protection in most studies. , In contrast, results from a few studies suggested a possible increased risk of A(H1N1)pdm09 virus infection among those vaccinated only with the seasonal A(H1N1) vaccine. Similarly, pandemic strain-specific vaccines were produced for pandemic responses in 1957–1958 and 1968–1969. A supplemental monovalent A/Taiwan/1/1986 (H1N1) vaccine was also produced to respond to emergence of an antigenically drifted strain of A(H1N1) in 1986. , Finally, a monovalent vaccine was produced and administered in the U.S. after the emergence of a novel A(H1N1) swine origin virus in 1976, based on fears that the virus was a pandemic threat. The emergence of antigenically drifted A(H3N2) viruses in 2014-2015, and subsequent seasons, with resulting low vaccine effectiveness renewed interest in developing the ability to produce monovalent or multivalent vaccines rapidly to respond to seasonal threats and to respond to pandemic threats with more rapid vaccine production.
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