As part of the family Orthomyxoviridae, influenza viruses are single-stranded RNA viruses with 3 types: A, B, and C. Influenza A viruses circulate in more than 18 mammalian species (including pigs and humans, although the main reservoir is aquatic wildfowl, including migratory birds) and are responsible for all known major epidemics and pandemics [3]. The influenza A virus genome contains 8 separate gene segments that have the ability to “reassort” or “mix” with other influenza A virus gene segments and thus “shift” antigenic characteristics [3,5]. These viruses are classified according to the subtypes of surface proteins, hemagglutinin (HA) and neuraminidase (NA) that they possess. HA is a surface glycoprotein essential for viral binding and entry into host cells. HA contains the primary epitopes for protective neutralizing antibodies, whereas NA has a somewhat lesser role in protective immunity and is primarily required for viral release [6]. Thus antibody against HA confers protection against infection and illness whereas antibody against NA can reduce the severity of illness. Annual changes in the HA epitopes lend themselves to a “drift” in protective immunity to circulating strains, hence the need for yearly review of the antigenic content of circulating influenza viruses. Pandemics occur when influenza viruses with HA for which there is little or no protective immunity emerge in the human population and transmit virus efficiently from person to person.

Since the global influenza A(H1N1) virus pandemic of 1918 (Spanish flu), influenza virus gene reassortment has been well documented and observed to occur frequently between human virus subtypes, between human and avian, and among avian influenza viruses [7,8]. Such reassortments led to the global pandemics of 1957 (H2N2) (Asian flu) and 1968 (H3N2) (Hong Kong flu) [8,9]. To have an idea of the magnitude of these epidemics, more Americans died as a result of the 1918 (Spanish flu) pandemic than were killed during World Wars I and II, the Korean, Vietnam, Gulf, Afghanistan, and Iraq wars combined [10].

Nearly all human influenza A infections worldwide since 1918 have been caused by descendants of the 1918 pandemic virus [7]. While influenza A(H1N1) viruses continue to circulate among humans, seasonal epidemics of influenza A virus from 1968 to 2009 were dominated by A(H3N2) virus variants generated by antigenic drift. However, in early April 2009 a new influenza A(H1N1) virus (originally referred to as swine-origin influenza A virus) emerged among humans in California and in Mexico, quickly spreading worldwide through human-to-human transmission, and generating the first influenza pandemic of the twenty-first century. Molecular studies of the new influenza A(H1N1) pandemic virus genome showed that it was antigenically unrelated to human seasonal influenza viruses but genetically derived from several viruses which had been circulating in pigs for a long time [8]. Initial transmission to humans is believed to have taken place at least several months before recognition of the first outbreak, and phylogenetic data suggest that the reassortment of swine lineages may have occurred years before emergence in humans. The 2009 H1N1 is a quadruple-reassortant virus containing gene segments from North American as well as Asian and European swine influenza viruses, some gene segments from North American avian influenza viruses, and one gene segment from a human influenza virus (Fig 1) [3–8]. During the current epidemic, however, there was no evidence that swine were playing any role in the epidemiology or in the worldwide spread of the virus in human populations [9].

Fig. 1 Emergence of influenza A (H1N1) viruses from birds and swine into humans. The diagram shows the important events and processes in the emergence of influenza A (H1N1) viruses during the past 91 years. Avian, swine, and human populations are represented in the top, middle, and bottom of the diagram, respectively. Epidemic or zoonotic viruses are shown as wide horizontal arrows (white for avian viruses, light blue or pink for swine viruses, and dark blue for human viruses). Cross-species transmissions are shown as vertical dashed lines, with thick lines for transfers that gave rise to sustained transmission in the new host and thin lines for those that were transient and resulted in a self-limited number of cases. Principal dates are shown along the bottom of the diagram. The disappearance of H1N1 in 1957 most likely represents competition by the emerging pandemic H2N2 strain in the face of population immunity to H1N1. The reemergence in 1977 is unexplained and probably represents reintroduction to humans from a laboratory source.

(From Zimmer SM, Burke DS. Historical perspective—emergence of influenza A (H1N1) viruses. N Engl J Med 2009;361(3):279–85; with permission.)

Novel influenza A(H1N1), henceforth referred to as 2009 H1N1, for the most part presented as a mild, self-limiting upper respiratory tract illness with (or at times without) fever, cough, sore throat, body aches, fatigue, chills, rhinorrhea, conjunctivitis, headache, and shortness of breath [9,11]. Up to 50% of patients had gastrointestinal symptoms at presentation including diarrhea and vomiting. The spectrum of clinical presentation varied from asymptomatic cases to primary viral pneumonia resulting in respiratory failure, acute respiratory distress, multiorgan failure, and death [12]. While fewer than 1% of estimated cases of 2009 H1N1 in the United States resulted in hospitalization, a quarter of those hospitalized required admission to the intensive care unit (ICU), and more than half required mechanical ventilation. The presence of underlying conditions was common among hospitalized patients; up to 60% of children, and 83% of adults admitted with 2009 H1N1 infection had at least one underlying chronic medical condition (CMC) (asthma, diabetes, cardiovascular disease, neurologic and developmental disorders, the latter 2 being more common in children). Eleven percent of hospitalized adults with 2009 H1N1 were pregnant [13].

The United States experienced its first wave of 2009 H1N1 pandemic activity in the spring of 2009, followed by a second wave of 2009 H1N1 activity in the fall. Activity peaked during the second week in October and then declined quickly to below baseline levels in January. The early increase in flu activity in October is in contrast to nonpandemic influenza seasons. From April 2009 to April 2010, a total of 61 million cases were reported, estimated range 43 to 89 million, with an estimated 195,000 to 403,000 hospitalizations and estimated deaths 8870 to 18,300 [14].

In the United States reports from around the country for pediatric cases seemed to follow a common theme. In California 345 children younger than 18 years with laboratory-confirmed 2009 H1N1 were reported over a 3-month period. The median age was 6 years; hospitalization rates were highest in infants younger than 6 months (13.9 per 100,000) versus overall rates (3.5 per 100,000 per 110 days). Two-thirds (230; 67%) had comorbidities. More than half (163 of 278; 59%) had pneumonia, 94 (27%) required intensive care, and 9 (3%) died; in 3 fatal cases (33%), children had secondary bacterial infections. More than two-thirds (221 of 319; 69%) received antiviral treatment, 44% (88 of 202) within 48 hours of symptom onset [15]. Similar numbers have been reported from other parts of the country [16].

In the authors’ own hospital in Northeast Florida, of the 119 hospitalized children, 25 (21%) were admitted to the pediatric ICU and 94 (79%) were admitted to the general medical ward [17]. Mean age was 6.4 years with 52 (44%) patients younger than 5 years. More than 70% of patients had at least one CMC, with the 3 most common being pulmonary, immunosuppression, and neurodevelopmental. The incidence of microbiologically proven coinfections and mortality rate were 6.7% and 0.8%, respectively. Comparison showed statistically that patients in the pediatric ICU had a significantly higher rate of CMCs, complications, and longer length of stay than patients admitted to the general medical ward. Minority populations also seemed to be affected disproportionately. This result may be partly related to the fact that they seemed to suffer more from underlying conditions, putting them at higher risk [18].

Review of reports published from countries in both the northern and southern hemispheres corroborated reports from across the United States that 2009 H1N1 occurred more frequently in young and middle-aged adolescents followed by older children and adolescents [19,20]. This course differs from that of seasonal influenza, which tends to affect people at the two extremes of life, namely the very young and the elderly. It is hypothesized that elderly individuals may have substantial levels of protective antibody against 2009 H1N1 due to past encounters with influenza virus with antigenic epitopes similar to the pandemic strain. Surveys of serum collected before 2009 showed that 4% of United States residents born after 1980 had preexisting neutralizing antibody titers of ≥40 against 2009 H1N1 whereas 34% of those born before 1950 and 57% of those born before 1940 had neutralizing antibody titers of ≥80 [21]. Fatal outcomes were seen at any age, however, and were more frequent in those with an underlying CMC.

Groups at risk for particularly severe infection included pregnant women as well as those with obesity. In the United States more than one-third of pregnant women with confirmed 2009 H1N1 infection had to be hospitalized because of acute respiratory distress syndrome. Pregnancy is known to increase the risk for severe influenza infection because of the physiologic changes of decreased pulmonary tidal volume and increased cardiac output. Suppressed T-helper cell-mediated immune responses also impair maternal responses to infection with several viruses. Seasonal influenza related hospitalization in healthy pregnant women occurs at a rate of 1 to 2 per 1000, a risk that is 18-fold greater than that for healthy nonpregnant women [22]. Obese individuals may also have been at increased risk related to changes in physiology as a result of altered body composition. It should also be noted that while the vast majority of cases reported in the literature were those of hospitalized patients, many cases of 2009 H1N1 influenza probably remained unrecognized in the community with a mild unrecognized respiratory illness; therefore, the true extent of the pandemic may actually be underreported.

The propensity to primarily affect children and young adults as well as its rapid spread made the 2009 H1N1 virus unique from other reassortant viruses. One theory is that the H1N1 virus binds α2,3-sialic acid receptors found on the surface of cells located deep in the lungs that seasonal influenza virus cannot bind, suggesting why people with the pandemic influenza seemed to experience more severe pulmonary symptoms [23].

The development of a vaccine against 2009 H1N1 was a top priority for public health officials globally. The threat of a possible increase in pathogenicity through further reassortment with avian or human virus strains as well as the total lack of cross-immune reactivity observed between the 2009 H1N1 and seasonal influenza virus strains (which made the 2009 seasonal vaccine ineffective against the 2009 H1N1 virus) were just two of the reasons why this became a global emergency.

Production of a pandemic influenza vaccine, however, raised several challenges, and public health officials were faced with several daunting issues as they began to make preparations for a vaccine against 2009 H1N1. These problems included ensuring that sufficient seasonal influenza vaccine would still be available before the start of seasonal influenza. This in turn required estimating with accuracy the production capacity of different producers for both seasonal and pandemic influenza vaccines. In addition, early on it was not clear whether one or two doses of pandemic vaccine would be required to induce full protection. Further, because influenza vaccines are made using eggs, it was imperative that there be a sufficient supply of healthy poultry and ultimately healthy eggs.

Influenza vaccines are licensed based on immunogenicity and not efficacy. Seasonal influenza vaccines contain 3 strains: A(H1N1), A(H3N2), and influenza B. Antibodies specific to HA are believed to be the best correlate of protection against influenza virus protection, and are the primary end point used to determine vaccine immunogenicity. The accepted correlate of protection is a hemagglutination inhibition (HI) titer of 1:40 or more (this test measures the ability of serum to compete with the binding of influenza virus to red blood cells) [24]. Influenza vaccines are made using the same reassortment process that leads to pandemic strains [25]. A virus seed strain adapted for growth in eggs using reassortment techniques is made and then serially passaged in eggs. This process gives way to the development of a high growth variant. This process clearly is extremely time consuming, depends on the egg supply, and is fraught with other technical challenges [26]. Cell culture–based vaccines may eventually be the way to overcome these issues.

Preliminary reports from a study done in Australia indicated that a single 15-μg dose of an inactivated split influenza A 2009 H1N1 vaccine induced a HI assay titer of 1:40 or more in 95% of 18- to 64-year-old healthy, nonpregnant subjects [27]. The robust immune response observed in the 18- to 49-year-old volunteer cohort was surprising. The findings suggested that there may be some cross-protection from previous exposure to antigenically drifted strains of H1N1 subtype. In addition, 2009 H1N1 shares 3 gene sequences with circulating seasonal H1N1, suggesting that there was more similarity between the 2009 H1N1 virus and the prevailing seasonal virus strains than had been recognized. Similarly, another randomized, observer-blind, age-stratified, parallel group study in 370 healthy infants aged 6 months to children under 9 years old in Australia, using 2 doses of either 15 μg HA or 30 μg HA monovalent, unadjuvanted 2009 H1N1 vaccine showed that a single 15-μg dose was immunogenic in children in this age group. No significant adverse events were reported [28].

In a United States phase 2 trial on 410 children and 724 adults who received a single dose (15 μg HA) of inactivated 2009 H1N1 vaccine, protective serologic titers of greater than 1:40 were detected at 21 days after vaccination in 45% to 50% of 6- to 35-month-old infants, 69% to 75% of 3- to 9-year-old children, 95% to 100% of 18- to 64-year-old adults, and 93% to 95% of adults older than 64 years. No vaccine-related severe adverse events were reported, but about 50% of every age and vaccine group reported injection-site and systemic reactions with no noticeable differences in the vaccine as compared with the placebo group [29]. Similarly, a multicenter, double-blind, randomized trial on 12,691 individuals 3 years of age and older in China receiving a single dose (7.5 μg HA) of a split virion 2009 H1N1 vaccine showed that protective serologic titers were detected on day 21 in 76.7% of 3- to 12-year-old children, 96.8% of 12- to 18-year-old adolescents, 89.5% of 18- to 60-year-old adults, and 80.3% of adults older than 60 years. In children, the administration of a second dose of the 7.5-μg formulation increased the seroprotection rate to 97.7%. Adverse reactions were mild to moderate [30].

Most recently another phase 2, multicenter, randomized, placebo-controlled, observer-blind, clinical trial using 2009 H1N1 vaccine in 1313 young adults (18–64 years) and older (≥65 years) conducted in 11 sites across the United States demonstrated that a single 7.5-μg dose of a monovalent, unadjuvanted 2009 H1N1 vaccine induced protective HI antibody levels in adults of all ages, including elderly adults [31]. Also, at baseline, 28.8% of young adults (18–64 years), 43.9% of younger elderly adults (65–74 years), and 62.9% of very elderly adults (≥75 years) had HI titers to 2009 H1N1 vaccine. Both older age (≥75 years) and receipt of the seasonal influenza vaccine in the previous season contributed independently to the antibody titer at baseline. Other studies in adults and children also suggest that receipt of seasonal influenza vaccine did have some cross-protection against 2009 H1N1 [32–35]. The Centers for Disease Control and Prevention (CDC) recommends immunization against both seasonal and 2009 H1N1 infection [36].

Given the safety and immunogenicity of the 2009 H1N1 vaccine in multiple trials around the world as well as the documented increased risk of complications from influenza and influenza-related illness, vaccination during pregnancy as well as in individuals with CMCs was considered high priority during the pandemic [37,38]. Vaccination of pregnant women was also seen as an effective strategy to prevent infection in infants too young to be vaccinated [39,40]. Health care workers were another group targeted for priority vaccination during the first round of immunizations. In fact, mandatory 2009 H1N1 vaccination was ordered in New York State for health care workers who had direct contact with patients or who had the potential to expose patients to the seasonal and 2009 H1N1 influenza. Ultimately this order was rescinded because of a shortage of both seasonal and 2009 H1N1 vaccine and opposition from some professional organizations. This mandatory vaccination policy raised several ethical questions and since then has come under much scrutiny [41]. Recently the American Academy of Pediatrics (AAP), the Society for Healthcare Epidemiology of America (SHEA), and the Infectious Diseases Society of America (IDSA) endorsed mandatory vaccination of health care workers to reduce the risk of infection among patients and employees [42,43]. The only exceptions would be people with medical contraindications for receipt of the vaccine. It was noted that the benefits of immunization would include prevention of disease from health care workers to patients, decrease health care workers’ risk of infection, create herd immunity, prevent excessive absenteeism during outbreaks, and set an example among the general public regarding the importance of immunization. Other priority groups included individuals with an underlying cardiovascular or respiratory medical condition including asthma, autoimmune disorders, and diabetes, as well as young children.

Studies of intranasal, live-attenuated, monovalent 2009 H1N1 influenza vaccine in children and adults have also demonstrated similar safety and immunogenicity when compared with similar seasonal influenza vaccine [44].

That it is possible to induce protective antibody levels against A(H1N1) infection in adults within 2 weeks of administration of a single dose of vaccine has now been confirmed with every pandemic H1N1 vaccine tested, whether split-inactivated vaccines, or whole virion vaccines. The same one-dose schedule applies to intranasal live-attenuated influenza virus (LAIV) vaccines. The Advisory Committee on Immunization Practices (ACIP) and AAP have recommended that young children should receive a 2-dose schedule, as is the case for seasonal influenza vaccines, but immunogenicity data from the aforementioned clinical trials indicate that a single dose induces appropriate levels of immune responses.

The safety of the 2009 H1N1 vaccines continues to be thoroughly monitored. Current data show that the vaccines are well tolerated and behave just as the corresponding seasonal influenza vaccines in terms of safety and lack of severe adverse events. It is of importance that the 2009 H1N1 vaccines are manufactured in exactly the same way as the seasonal influenza vaccines and therefore are not really “new” vaccines. A small number of Guillain-Barré syndrome (GBS) cases have been reported to be temporally associated after H1N1 vaccine administration in large-scale vaccination campaigns, but they all reverted quickly [45,46]. Clinical trials are still in progress in certain at-risk subpopulations.

Vaccination against 2009 H1N1 influenza was first implemented in China, followed by a large number of countries [47]. In the United States, the Food and Drug Administration (FDA) licensed the first 2009 H1N1 vaccines on September 15, 2009 [48]. None of these vaccines contained any adjuvants. The WHO was responsible for coordinating the effort to ensure adequate supply and access to 2009 H1N1 vaccine in underresourced countries.

A total of 26 vaccine manufacturers from America, Europe, Russia, Australia, and Asia have now developed or are presently developing pandemic A(H1N1) vaccines, whether inactivated whole-virus vaccines, split inactivated vaccines, subunit vaccines, live-attenuated vaccines, or other formulations. The silver lining to this pandemic was the emergence of several new vaccine manufacturers in China, India, Thailand, and South America [49].

Despite the widespread publicity as well as education campaigns by the CDC and state and local public health officials, public attitudes toward 2009 H1N1 immunization at best remained lukewarm both in the United States and globally. Despite all the available safety data from multiple studies the public, including individuals at high risk, remained skeptical about vaccine safety [50–54]. This situation continues to highlight the need for ongoing education and public health campaigns. Immunization remains the key to the control of future disease outbreaks. Concerns over the development of resistance to antiviral medications currently used for the treatment of influenza are beyond the scope of this discussion, yet remain another important reason why prevention is so critical. One recent study suggested that any practice visits during October through January as well as evening/weekend influenza vaccine clinics seemed to improve influenza vaccine uptake in young children. This study looked at simultaneous practice and child characteristics as well as practice strategies that are associated with influenza vaccination in geographically different states [55].

Other issues that have implications for future public health policy regarding influenza immunization include school-based immunization as well as immunization within households. There are mixed data regarding transmission within households. It does not appear that 2009 H1N1 transmission was any different from seasonal influenza [56,58]. Similarly, transmission within schools also depended on several factors including rapid identification of cases, implementation of prophylaxis, and school closure in certain instances [59]. It is imperative that we consider the implications of secondary cases due to household and school contacts when formulating public health policy during future pandemics and when formulating future strategies for immunization and containment [60,61].

In the United States, 2009 H1N1 remained the dominant circulating virus during 2009. Few seasonal influenza viral infections were reported, the most being due to influenza A/H3N2 or influenza B. Seasonal influenza A/H1N1 almost seemed to disappear. Similar trends were seen worldwide [62].

Immunization recommendations for the current influenza season include immunization of all high-risk groups previously identified for seasonal influenza immunization (Box 1) [63,64]. An algorithm for immunization in children who may or may not have received the 2009–2010 seasonal as well as 2009 H1N1 vaccine is also outlined in the policy statement by the AAP. Recommendations that are new this year include expansion of routine immunization to include adults 19 to 49 years regardless of any underlying medical condition. Vaccines available for the 2010–2011 influenza season are listed in Table 1.

Table 1 Currently available influenza vaccines, 2010–2011 season