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Who are the recommended target groups for receiving the novel influenza A (H1N1) 2009 monovalent vaccine according to the Centers for Disease Control and Prevention?

Introduction
A novel strain of influenza A (H1N1) was identified in April 2009 and has spread rapidly throughout the country and across the world.¹ This strain, is both antigenically and genetically unique when compared with the seasonal influenza viruses typically responsible for infection.^1,2 On June 11, 2009 the World Health Organization (WHO) declared a pandemic based on uncontained transmission of this virus in various areas of the world.¹ According to the Centers for Disease Control and Prevention (CDC), 43,771 confirmed or probable cases of this novel H1N1 influenza have been reported in the United States from April 15, 2009 to July 24, 2009.³ Through the end of July, novel H1N1 infection has resulted in 5,514 hospitalizations and 353 deaths.¹ Due to the large number of identified cases and hospitalizations, development of a vaccine geared toward this specific strain of influenza became a priority. The CDC’s Advisory Committee on Immunization Practices (ACIP) recently released recommendations for subsets of the population who should preferentially receive the vaccine when it becomes available. Clinicians are encouraged to familiarize themselves with the full document found at http://www.cdc.gov/h1n1flu/vaccination/acip.htm.

Novel Influenza A (H1N1)
Influenza A is a family of single stranded RNA influenza viruses that have a genome comprising 8 segments.² Nomenclature for influenza A viruses is guided by subtypes of 2 envelope glycoproteins: hemagglutinin (H) and neuraminidase (N). These proteins are the target antigens responsible for mounting an immune response. In total there are 16 hemagglutinin and 9 neuraminidase subtypes identified.

Even though influenza viruses are known to affect humans, pigs, horses and dogs, the common reservoir for all influenza viruses is aquatic birds.² Genetic re-assortment that incorporates unique avian hemagglutinins or neuraminidases into the make-up of influenza strains already known to cause illness in humans is a major culprit in the creation of the virulent influenza strains responsible for pandemics.

Interestingly, the origin of a similar H1N1 strain of influenza A has a history that dates farther back than a few months.² So-called “classical” H1N1 strains of influenza have been circulating in swine since 1918, the time of the Spanish influenza pandemic. A genetic reorganization among this “classical” swine H1N1, the avian-like Eurasian swine H1N1, and the North American H3N2 lineage is thought to be a precipitating event in the emergence of the novel H1N1 influenza. The resulting virus is believed to have been harbored in swine and rearranged again with 1 or more additional swine-origin strains. Unfortunately, the known genetic information for this variation of influenza has not lead to identification of an immediate precursor at this time.

H1N1 Infection
Signs and symptoms of infection with novel H1N1 influenza have been similar to the hallmarks of seasonal influenza respiratory illness such as fever, cough, and sore throat.⁴ Diarrhea and vomiting were experienced by 25% of infected persons according to data from 642 confirmed cases. Laboratory measures taken to confirm cases of novel H1N1 influenza include both viral culture and real-time reverse-transcriptase polymerase chain reaction (RT-PCR).

Epidemiologic data indicate that this particular strain of influenza most frequently affects children and young adults.¹ A median age of infection of 12 years, with the highest incidence reported in persons 5 to 24 years old, has been confirmed worldwide. Individuals aged 65 years and older represent the smallest portion of novel H1N1 infections to date. This drastically contrasts what is illustrated annually with seasonal influenza.

Hospitalizations have occurred most commonly in children younger than 4 years, however the median age of hospitalization has been 20 years.¹ For the reported deaths, a statistic that remains low in comparison to annual deaths from seasonal influenza, the median age is 37 years. Conversely, of annual seasonal influenza infections, persons 65 years and older represent an estimated 60% of hospitalizations and 90% of deaths. Through the end of July 2009, the elderly only represent 5% of hospitalized cases and 8% of novel H1N1-related deaths.

Medical risk factors have been identified for H1N1 influenza.¹ These are based on case series illustrating subsets that account for an increased percentage of documented infections. One of the most profound groups at risk is pregnant women. Pregnancy carries an estimated 4-fold greater risk for becoming infected with novel H1N1 influenza. Other factors that are associated with high risk of infection and complications include persons who are with inadequate immune function or those with chronic heart, liver, lung, or kidney disease.

Vaccination
It has long been known that vaccination is the most effective method in the prevention of seasonal influenza illness and related complications.¹ Almost immediately following the identification of this novel H1N1 strain, vaccine manufacturers (along with public health and regulatory bodies) initiated development of a 2009 H1N1 influenza vaccine. It should be noted that this vaccine is different from the seasonal influenza vaccine, which does not provide protection against novel H1N1 influenza. Vaccines used to prevent seasonal influenza promote immunologic protection against what are determined to be the most likely seasonal influenza strains causing illness in a given year. Unlike seasonal influenza vaccines, the novel H1N1 influenza vaccine is monovalent and therefore only induces immunologic response to a single strain of influenza. On September 15, 2009 the Food and Drug Administration (FDA) approved 4 formulations of the vaccine: 3 are inactivated injectable forms, and 1 is a live attenuated intranasal preparation.⁵ None of the approved vaccines include adjuvants.

Efficacy for vaccination was originally demonstrated in a single center study, performed by Clark and colleagues, including 175 adults using both M59-adjuvanted and non-adjuvanted forms of a monovalent influenza A vaccine.⁶ The M59-adjuvant is an oil-in-water emulsion added to vaccine preparations to enhance immunogenicity and aid in formation of cross-reactive antibodies with the aim to protect against possible viral antigen drift. Addition of an adjuvant allows for lower doses of the vaccine to be used, which would be helpful in manufacturing enough vaccine to cover a larger portion of the population.⁵ Results from an interim analysis of 7.5 mcg dose of MF59-adjuvanted vaccine indicated that this formulation produced adequate response by days 14 and 21 after administration.⁶ Response, measured by hemagglutinin-inhibition and microneutralization assays, was to be assessed at days 0, 14, 21 and 42. At day 21, 76% of patients had achieved seroconversion based on the hemagglutinin-inhibition assay and 92% had achieved seroconversion based on microneutralization assay. This prompted another study to evaluate a single dose regimen.

In a randomized, observer-blinded, phase 2 study conducted by Greenberg and colleagues the efficacy of 2 different doses of novel influenza (H1N1) vaccine was tested.⁷ Two hundred forty healthy, non-pregnant adults between 18 and 64 years were randomized to receive either 15 mcg or 30 mcg non-adjuvanted hemagglutinin antigen vaccine for 2 scheduled doses on days 0 and 21. Antibody titers were drawn at baseline and on day 21 with a desired vaccine-induced titer of 1:40 or greater. At the day 21 analysis, 96.7% of patients who received the 15 mcg dose and 93.3% of patients who had received the 30 mcg dose developed titers equal to, or exceeding, 1:40. Due to the majority of patients reaching appropriate levels of antibody, it was concluded that a single, one time dose of the novel H1N1 influenza vaccine provides adequate protection. However, it is currently recommended that children younger than 10 years should receive two doses of vaccine separated by approximately 1 month, since this group does not mount as robust of an immune response.⁵

Adverse effects reported in the aforementioned studies were mostly mild in nature. ^6,7 These effects were similar to those seen after administration of the seasonal influenza vaccine: pain or tenderness at the injection site, headache, and malaise or myalgias. It is also important to note that due to the use of egg-media in the manufacturing process, use of the novel H1N1 influenza 2009 monovalent vaccine should be avoided in persons with severe allergies to chicken eggs.

ACIP Recommendations
The ACIP has developed a list of target groups considered most at risk of contracting or transmitting this particular virus.¹ The logic in creating these recommendations is to efficiently and effectively control the spread of H1N1 influenza by preventing infection in those most at risk for illness and transmission. These groups are directly drawn from the medical and demographic-associated rates of infection discussed above, and include:

By providing vaccination individuals in the above categories, it is projected that 159 million persons will be immunized against novel H1N1 influenza.¹ In case of limited vaccine supply the recommendations become stricter with respect to categories 4 and 5. If shortages are reported, it is recommended to limit category 4 to infants and children from 6 months to 4 years and to then alter category 5 to include those aged 5 to 18 years with medical conditions associated with greater risk of influenza-related complications. This decreases the number of covered persons to 42 million. Depending on state and local regulation, vaccination may be expanded to include anyone falling outside the 5 target groups based on availability and demand. In fact, the ACIP recommend allowing the opportunity for vaccination to all persons from 25-64 years of age. Due to the limited risk seen in persons aged 65 and older, it is not recommended for this age group until the demand for all other subsets of the population are met.

Vaccine Availability
Recently, the American Society of Health-System Pharmacists released information from the CDC indicating that 3.4 million doses of the intranasal novel H1N1 vaccine will be available starting in the first week in October 2009. It is important to recognize that this formulation is not appropriate for all target risk groups. Due to the live nature of the intranasal preparation, it is only indicated for use in healthy adults. This excludes persons from 2 major target groups: pregnant women and children less than 2 years of age. At this time the FDA is awaiting more information from the manufacturers before distribution of injectable vaccine will begin.

Summary
Recommendations from the ACIP were recently made regarding target groups who should be offered novel H1N1 influenza 2009 monovalent vaccine from the initial supply. This is important to take into consideration because of the rapid spread of this newly identified strain of influenza, which is thought to have evolved though a genetic rearrangement of genetic material from “classical” swine H1N1, the avian-like Eurasian swine H1N1, and the North American H3N2 lineage. Symptoms of novel H1N1 influenza are similar to manifestations of seasonal influenza, except that a younger age group appears to be more susceptible to this particular influenza strain. The ACIP developed 5 target groups that should preferentially receive the novel influenza A vaccine as it becomes available. These groups are as follows: pregnant women, those who reside with or care for infants less than 6 months of age, all health care and emergency services personnel, individuals aged 6 months to 24 years, and those 25 to 64 years old with co-morbid conditions associated with high risk of experiencing influenza-related complications. It is important to follow these guidelines in order to vaccinate as many high-risk persons as possible in the shortest period of time.

For the latest information regarding the novel H1N1 influenza vaccine please visit http://www.flu.gov or http://cdc.gov/h1n1flu/vaccination/public/vaccination_qa_pub.htm.

References

By: Kelly Valla, PharmD