Influenza A is one of the very few respiratory viruses for which effective vaccination exists. Each year strains of virus identified as those likely to be the circulating strains for that particular influenza season are used to produce the seasonal influenza vaccine. Currently there are two types of vaccine. The first is a trivalent, inactivated vaccine which is injected into the muscle of the upper arm or thigh. This trivalent vaccine contains two influenza A strains and one influenza B strain. The 2009–2010 vaccine includes A/Brisbane/59/2007(H1N1)–like, A/Brisbane/10/2007(H3N2)–like, and B/Brisbane/60/2008–like. It can be used for people six months of age or older. The second is a live, intranasal vaccine using the same strains, which can be used for healthy people 2-49 years of age.
In 2007, a H5N1 vaccine was approved by the United States Food and Drug Administration (FDA). This monovalent vaccine uses the A/Vietnam/1203/ 2004 influenza strain and is not commercially available, but will be stockpiled by the federal government to be used in the event of a pandemic.
Currently a monovalent vaccine using the A/California/07/2009 (H1N1) strain was approved by the FDA and World Health Organization (WHO) for prevention of novel H1N1 in an inactivated, adjuvanted form and also in a live attenuated intranasal formulation.
A recent Cochrane analysis of vaccines for preventing seasonal influenza in healthy adults included 48 reports: most of them (38, including 57 sub-studies) were clinical trials providing data about effectiveness, efficacy and harm of influenza vaccines and involved 66,248 participants. Another eight were comparative nonrandomized studies and tested the association of the vaccines with serious harmful effects. The effectiveness of inactivated parenteral vaccines was 30% (95% CI 17-41%) against influenza-like illness, and the efficacy was 80% (95% CI 56-91%) against influenza when the vaccine matched the circulating strain and circulation was high; it decreased to 50% (95% CI 27-65%) when it did not match . A recent prospective study compared the efficacy of inactivated and live attenuated influenza vaccines and found that the latter was less efficacious . A new development is virosomal influenza vaccines. Virosomes consist of reconstituted influenza virus envelopes formed by purified neuraminidase (NA) and hemagglutinin (HA) proteins anchored in the membrane, but lacking the genetic material of the native virus. The efficacy was shown to be superior and the side-effects minor compared to the established vaccines . However, larger clinical trials with these vaccines should be conducted before drawing final conclusions.
Immunosuppressed persons form a special group at higher risk of influenza-associated complications. They show a general trend toward impaired humoral vaccine responses. Currently, longitudinal data are largely lacking. However it seems that these persons can be safely vaccinated. There is only one randomized clinical trial of HIV-infected patients, which showed high vaccine efficacy, thus supporting the recommendation for vaccination . In this rather small study, 102 patients with HIV-1 infection were randomized to receive influenza vaccination (n = 55) or saline placebo (n = 47). Ten placebo recipients but none of the vaccine recipients had laboratory-confirmed symptomatic influenza (p <.001) [protective efficacy, 100% (95% CI, 73% to 100%)]. There was no effect on plasma HIV-1 RNA levels or CD4+ cell counts. The authors concluded that influenza vaccination is highly effective in HIV-1-infected persons and does not seem to be associated with substantial changes in viral load or CD4 cell count.
Annual vaccination against seasonal influenza is recommended for all children beginning at age six months and continuing to the 19th birthday. Vaccination for adults is especially recommended for persons at high risk of complications from influenza. The current CDC (Centers for Disease Control and Prevention) recommendations for vaccination are summarized in Table 1.
There are also contraindications for seasonal flu vaccination, including persons who have a severe allergy to chicken eggs, persons who have had a severe reaction to a previous influenza vaccination, persons who have developed Guillian-Barré syndrome within six weeks of getting an influenza vaccine, children less than six months of age (influenza vaccine is not approved for this age group), and persons who have a moderate to severe illness with a fever (they should wait until they recover to get vaccinated).
The nasal-spray flu vaccine is an option for healthy persons between 2 and 49 years of age. Pregnant women are excluded. Children aged two to eight years not previously vaccinated with influenza vaccine should receive two doses at least one month apart; all others need only one dose. The latest data available indicate that this vaccine is less efficacious than the inactivated vaccine .
The most common side-effects of the inactivated vaccine are soreness, redness or swelling where the infection took place, low-grade fever and malaise as well as aches. These signs and symptoms usually resolve within the first 48 hours. As the vaccine uses inactivated viruses or viral particles, it is impossible to be infected by the vaccine and to get the flu. Side-effects of the nasal live attenuated vaccine include rhinorrhea, wheezing, headache, nausea, myalgia and fever. Some persons shed virus after intranasal vaccination . The shedding was generally of short duration and at low titers and transmission was observed in only one person so far .
The current nH1N1 vaccine was approved by the FDA on September 15, 2009. It is being manufactured by four different companies. Detailed information about nH1N1 vaccine, including type of vaccine, hemagglutinin content and adjuvants used are presented in Table 2.
||TABLE 2. Current vaccines against pandemic influenza A (H1N1)
(This table is based on two tables in an article published on 15 October 2009 in Eurosurveillance, Volume 14, issue 41. The authors are: Johansen K, Nicoll A, Ciancio BC, Kramarz P. Pandemic influenza A (H1N1) 2009 vaccines in the European Union. Euro Surveill 2009;14:pii:19361. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19361)
The recommendation for administration of Celvapan, Focetria and Pandemrix is for two injections given three weeks apart. Fluval P may be administered only once. However, the European Medicines Agency (EMEA) has published a press release (Doc. Ref. EMEA/748707/2009) indicating that a single dose of Focetria and Pandemrix is able to trigger an immune response that may be sufficient to give protection against the H1N1 pandemic influenza in some age groups. For both vaccines, a single dose may be used in adults aged between 18 and 60 years and in children and adolescents (from age nine years for Focetria, and from ten years for Pandemrix). Pandemrix may also be used as a single dose in the elderly. For certain groups, such as younger children and immunocompromised patients, the recommendation remains that two doses should be given, to ensure that the immune system responds adequately to the vaccination. Further data will become available in the coming months. Data on Celvapan are still being assessed.
Side-effects reported by EMEA (Doc. Ref. EMEA/748707/2009) include mild symptoms such as fever, nausea, headache, allergic reactions and injection-site reactions, confirming the expected safety profile of the three vaccines. A very small number of cases of Guillain-Barré syndrome and fetal death have been reported in patients previously vaccinated with a pandemic vaccine. The EMEA is still in the process of gathering relevant information and evaluating the data. However, on the basis of the available information, there is no evidence to link these events to the vaccines.
Initially, target groups were identified to be vaccinated first , because nH1N1 vaccines were limited (Table 3). In the meantime the supplies increased and many persons belonging to the target groups have been vaccinated, so that now it is recommended to offer nH1N1 vaccination to everyone .
There has been a discussion about partial protection from nH1N1 by the seasonal vaccine. In a preliminary study it was reported that seasonal influenza vaccination confers partial protection against novel H1N1 infection . In a multivariate model, nH1N1 was independently associated with trivalent inactivated vaccine (odds ratio 0.27, 95% CI 0.11-0.66); vaccine effectiveness was 73% (95% CI 34-89%). None of eight vaccinated cases died. However, these findings could not be reproduced in other studies. The CDC performed a case-cohort analysis using surveillance reports from eight US states of persons aged >18 years with confirmed nH1N1 illness during May-June 2009. Influenza vaccination coverage rates during the 2008-09 influenza season (September 2008-February 2009) were estimated. The overall vaccine effectiveness against pandemic virus illness after adjustment for age group and presence of chronic medical conditions that increase the risk for complications from influenza was -10% (95% CI -43% to -15%). In another study it was shown that a total of four out of 107 persons (4%) born after 1980 had preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children (0%) between the ages of six months and nine years, in 12% to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. Vaccination with nH1N1 influenza vaccine substantially boosted cross-reactive antibodies to nH1N1 in adults. The authors concluded that vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to nH1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies . A recent study from Australia on 223 patients with pandemic influenza supports the finding that no evidence of significant protection from seasonal vaccine against nH1N1 infection in any age group could be found .
Taken together, the current evidence does not support a significant effect of 2008--09 trivalent influenza vaccine in either decreasing or increasing the risk for nH1N1 illness. Therefore, the CDC and the Advisory Committee on Immunization Practices continue to recommend vaccination with both seasonal and pandemic influenza vaccines to prevent influenza illness during the 2009-10 influenza season in the United States .
The nasal-spray flu vaccine is an option for healthy people between 2 and 49 years of age. Pregnant women are excluded. Children age two years through nine years should receive two doses approximately one month apart; children, adolescents and adults age 10 through 49 years need only a single dose.
The FDA-approved H5N1 vaccine uses the A/Vietnam/1203/2004 influenza strain and is not commercially available. It has been stockpiled by governments to be used in the event of a pandemic.
There are a good number of studies proving efficacy and safety of H5N1 vaccination in all age groups. One of the biggest studies evaluated a 15-μg HA dose of a candidate oil-in-water emulsion-based adjuvant system (AS), adjuvanted split-virion H5N1 (AS-H5N1) vaccine, compared to a licensed seasonal influenza vaccine in 5071 healthy adults. Significantly more participants in the AS-H5N1 vaccine group reported general or local adverse events, with pain being the most common symptom in both treatment groups. Fewer than 1% of subjects withdrew from the study due to adverse events and no withdrawals were due to serious adverse events related to vaccination. The authors concluded that the safety and immunogenicity profile of the AS-H5N1 candidate vaccine can be considered clinically acceptable in the context of its use against pandemic influenza .
The immunogenicity of H5N1 vaccines was evaluated in a series of studies. In one of the biggest studies, 1206 Asian adults randomized to receive two doses of adjuvanted (3.75 μg HA) or diluent-mixed vaccines 21 days apart were investigated. After the second dose, 96.0% of vaccinees in the H5N1 group demonstrated a fourfold increase in neutralizing antibody titers against the vaccine strain A/Vietnam/1194/2004 and 91.4% against strain A/Indonesia/05/2005. HA-inhibiting antibodies (titer ≥1:40) against A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains were observed in 94.3% and 50.2% of subjects, respectively. The vaccine induced a high frequency of immune responses to the vaccine strain, allowed antigen sparing, and promoted cross-clade immunity .
The H5N1 vaccine is generally well tolerated and the most common side-effects include pain and tenderness at the injection site, headache, general ill feeling, and muscle pain, all comparable to the seasonal vaccine.
There are two FDA-approved classes of medication for prophylaxis and treatment of influenza A: the adamantanes (amantadine, rimantadine) and the NA inhibitors (zanamivir, oseltamivir). As a result of the pathophysiology of influenza infection and replication, all of these drugs have optimal activity within the first 48 hours after infection.
There are currently two approved adamantanes: amantadine and rimantadine. Both inhibit viral M2 ion channel protein activity, which is only present in influenza A. This blocks viral uncoating and reduces infectivity . Because of this mechanism, both drugs are ineffective against influenza B. The treatment benefit over symptomatic treatment alone in reduction of illness within 24 hours is marginal . Adamantanes are limited in use by their side-effects. Amantadine use is associated with neurotoxicity, resulting clinically in anxiety, nervousness, agitation, insomnia and other nervous effects. Rimantadine, the alpha-methyl derivative of amantadine, is four to ten times more active than amantadine and causes fewer central nervous system adverse effects . Further limitations include widespread resistance against adamantanes among different influenza A strains all over the world . Sixty-one percent of H3N2 isolates from Asia and 92% from the United States in 2006 were drug-resistant [19,20]. Resistance has also been reported for Asian H5N1 viruses. Only 20% of poultry-derived isolates in China, and none in Thailand, were sensitive to adamantanes [21-23]. According to WHO, adamantanes should not be used to prevent or treat H5N1 infections unless the infecting virus is known or likely to be sensitive . It is clearly advisable to follow yearly guidance recommendations based on surveillance data.
Concerning the recently emerged 2009 pandemic H1N1 viruses, all isolates tested for adamantane resistance at CDC have shown resistance .
Neuraminidase inhibitors interfere with late events in viral replication. They inhibit the budding of newly formed viral particles from infected host cells. It has been extensively shown that NA inhibitors should be administered as soon as possible because of their interference with viral replication, which is greatest soon after the onset of infection . Studies have clearly shown that administration 48 hours or later after the onset of infection results in significantly decreasing drug efficacy . Both of the NA inhibitors oseltamivir and zanamivir are effective against influenza A and B viruses .
A recent review analyzed the reduction of influenza-associated complications by NA inhibitors . In three randomized, controlled trials on zanamivir enrolling healthy children , healthy adults , and elderly and at-risk adults , complications were reduced in comparison to placebo by 30%, 33% and 71%, respectively. In three randomized, controlled trials on oseltamivir enrolling healthy children , healthy adults , and institutionalized elderly , complications were reduced in comparison to placebo by 40%, 40% (75 mg b.i.d.) or 67% (150 mg b.i.d.), and 85%, respectively. The authors concluded that NA inhibitors can reduce the incidence of influenza-associated complications, particularly in high-risk groups.
However, recently doubts were raised about the effectiveness and safety of oseltamivir . During the process of updating the Cochrane review of 2006, Jefferson et al  found several important inconsistencies. They were not able to reconstruct the evidence from a much-cited analysis by Kaiser et al  on which they had based their previous conclusions. This analysis was found to be funded by the drug’s manufacturer, Roche, and was based entirely on ten trials funded by Roche, only two of which had been published as articles in peer-reviewed journals . All of these trials were authored by Roche employees and paid academic consultants. The Cochrane reviewers could find no independently funded trials of oseltamivir in healthy adults . Further questions arose concerning which authors of the trials had actually seen the raw data, why the rates of influenza infection in the trials were so high, and why serious adverse events were under-reported .
In the current Cochrane review, Jefferson et al  concluded that they are not convinced that oseltamivir reduces the risk of complications and hospital admission in patients with influenza. This agrees with the current conclusions of the FDA and the recent health technology assessment performed for the United Kingdom’s National Institute for Health and Clinical Excellence (NICE). Both agencies conclude that there is insufficient evidence on complications . This has serious implications because antiviral drugs have played and will continue to play an important role during the management of current and future pandemics, and governments around the world have spent billions of dollars on a drug that the scientific community has found itself unable to judge .
Another important issue with NA inhibitors is drug-resistance, which concerns mainly oseltamivir. In Japan, almost 20% of children treated with oseltamivir were found to shed resistant seasonal H3N2 viruses . In Portugal, 20.7% of seasonal H1N1 viruses was observed to be oseltamivir-resistant in 2007/2008, which increased to 100% in 2008/2009 . The European Surveillance Network for Vigilance against Viral Resistance (VIRGIL), in collaboration with the European Influenza Surveillance Scheme (EISS), the WHO, and national influenza centers, reported oseltamivir resistance in 14% of European strains tested . Similarly, Influenza A/H1N1 virus H274Y mutants were found in 11.1% of samples from New York for 2007-2008, a level comparable to the 10.9% nationwide level reported by the CDC; in contrast, mutants were found in 17.4% of samples from Wisconsin .
According to WHO, oseltamivir resistance is rare in nH1N1. As of January 22, 2010, 206 cases of oseltamivir resistance have been reported. All of these viruses showed the H274Y mutation and all remained sensitive to zanamivir. Although the majority of reported cases are associated with oseltamivir treatment, cases of resistance have occurred in patients taking oseltamivir to prevent pandemic influenza infection . About one-third of the cases of oseltamivir-resistant H1N1 viruses have occurred in patients whose immune systems were severely immunocompromised, matching earlier reports . It is important to understand that, rather than emerging under selective pressure of drug use, as many antibiotic-resistant bacteria do and as has been the concern for influenza, the oseltamivir-resistant strain (H274Y) seems to be a natural, spontaneously arising variant .
Oseltamivir-resistant H5N1 viruses have also been recovered from patients in Southeast Asia [45,46]. It has been shown that H5N1 viruses with the H274Y substitution in NA that emerge during oseltamivir treatment do retain full susceptibility to zanamivir .
Resistance to zanamivir is significantly less frequent. This may be due to its limited use so far and to its pharmaceutical design. Zanamivir, as compared to oseltamivir, is more structurally similar to the natural substrate of neuraminidase and fits directly into the active site. For oseltamivir to fit into the neuraminidase active site, the amino acids there must undergo a conformational change to accommodate the drug’s hydrophobic side chain. Mutations preventing this rearrangement, including R292K, N294S, and H274Y, can lead to oseltamivir resistance but do not affect zanamivir susceptibility . Nevertheless, two distinct mutations within the neuraminidase gene that affect zanamivir activity have been identified in clinical isolates: the R152K mutation, identified in an influenza B virus isolated from a zanamivir-treated immunocompromised patient ; and recently a novel Q136K mutation .
The clinical use of zanamivir can be limited in severely ill patients who are unable to inhale it, or whose pulmonary infections are inaccessible to topical therapy . To circumvent this limitation, trials investigating an intravenous formulation of zanamivir are underway (www.clinicaltrials.gov).
It has to be pointed out that most people suffering from influenza will recover without complications and hence do not necessarily need antiviral treatment. However, persons at highest risk of influenza-related complications should be prioritized for treatment with influenza antiviral drugs this season (Table 4). Otherwise healthy children and adults with suspected influenza and symptoms of lower respiratory tract illness or clinical deterioration should also receive prompt empiric antiviral therapy, regardless of previous health or age. The recommended duration of therapy is five days.
Pre-exposure antiviral chemoprophylaxis is not recommended and should only be used in limited circumstances, and in consultation with local medical or public health authorities. In circumstances with ongoing risk of occupational exposure, the application of appropriate personal protective equipment is mandatory.
Post-exposure antiviral chemoprophylaxis generally should be reserved for people at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza. It can be considered for health care personnel, public health workers, or first-responders who have had a recognized, unprotected close-contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 or seasonal influenza during that person’s infectious period. However, use of recommended personal protective equipment and other administrative controls (e.g., having health care personnel stay home from work when ill, and triaging for identification of potentially infectious patients) should be used to reduce the need for post-exposure chemoprophylaxis among health care workers (http://www.cdc.gov/h1n1flu/antiviral.htm#recommendations). The duration of antiviral chemoprophylaxis is ten days after the last known exposure. Details of the dosing recommendations for treatment and prophylaxis are summarized in Table 5.
It has been simulated in a population dynamical model of pandemic influenza with treatment to include post-exposure prophylaxis of close contacts that, when transmissible resistant strains are present, post-exposure prophylaxis can promote the spread of resistance, especially when combined with aggressive treatment. It was further shown that, when treatment is maintained at intermediate levels, limited post-exposure prophylaxis provides an optimal strategy for reducing the final size of the pandemic while minimizing the total number of deaths . There are reports indicating a need for limiting the indications for post-exposure prophylaxis and to rapidly convert prophylactic (once daily) regimens to therapeutic (twice daily) regimens as soon as influenza-like symptoms develop in a patient receiving prophylactic treatment .
Previous vaccination is not a contraindication to antiviral drug treatment, and treatment recommendations parallel those for unvaccinated persons. Persons who are vaccinated with live attenuated influenza vaccines and who are given antiviral drugs within 48 hours before or up to two weeks after vaccination might not develop immunity and should be revaccinated .
A new NA inhibitor named peramivir has recently been developed. It has a significantly longer half-life than the approved drugs (22 hours) but poor oral bioavailability. Thus, it has to be administered by the parenteral route, and clinical trials investigating different doses and routes of administration are underway. In the meantime an Emergency Use Authorization (EUA) for peramivir for intravenous (IV) injection has been issued by the FDA based on safety and/or efficacy data from 1891 patients with acute uncomplicated seasonal influenza A . Under the EUA, treatment of adult patients with IV peramivir is approved only if: (1) the patient has not responded to either oral or inhaled antiviral therapy; (2) drug delivery by a route other than IV is not expected to be dependable or is not feasible; or (3) the clinician judges IV therapy is appropriate due to other circumstances. Treatment of pediatric patients is approved if either of the first two criteria apply (http://www.cdc.gov/H1N1flu/recommendations.htm#a).
Other treatment options
Treatment with anti-influenza virus antibodies could potentially be of clinical benefit especially in severe influenza by preventing the binding of virions to target cells and marking infected cells for destruction by complement or T cells. However, there is currently no immunoglobulin product in clinical use. The best clinical data we have so far go back to the 1918 pandemic . At that time severely ill patients were sometimes treated with whole blood, plasma or serum from convalescing survivors. A current review of these experiences found that the overall case fatality rate was lower in patients who received the products compared to those who did not (16% vs 37%) . From the current H5N1 outbreak we have limited experience with treatment of a severely ill H5N1 patient with plasma from a convalescent survivor .
There are several promising results from experimental studies extensively reviewed by Beigel et al . A recently discovered class of monoclonal antibodies (mAbs) able to neutralize an unprecedented spectrum of influenza virus subtypes may have the potential for future use in humans. The efficacies of CR6261, which is representative of this novel class of mAbs, and oseltamivir were assessed in mice. It was shown that a single injection with 15 mg/kg CR6261 outperforms a five-day course of treatment with oseltamivir (10 mg/kg/day) with respect to both prophylaxis and treatment of lethal H5N1 and H1N1 infections. Further preclinical evaluation of broadly neutralizing mAbs against influenza virus for the prevention and treatment of influenza virus infections seems to be justified . Importantly, better clinical data are warranted to better appreciate the possible future role of this approach.
Ribavirin (Virazole®) is a guanosine analogue licensed for the treatment of hepatitis C in combination with interferon-alfa and for aerosol therapy of respiratory syncytial virus infections in infants . The mode of action is both indirect, by lowering intracellular GTP levels through the inhibition of inosine 5’-monophosphate dehydrogenase, and direct, by interfering with transcription and genome replication . Thus, it is able to inhibit both RNA and DNA viruses. Drug resistance is rarely observed. In its intravenous form ribavirin can be used as a salvage therapy in severly ill influenza patients in which other treatment options failed. There is a case-report on three patients with severe influenza or parainfluenza virus infection . Use of high-dose ribavirin is associated with risk of hemolytic anemia and other side-effects, clearly limiting its use .
Substances under development
Recent developments in the field of influenza treatment include: viramidine, a prodrug of ribavirin which is now in Phase 3 trials for the treatment of hepatitis C; the pyrazine derivative T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), which is a broad-spectrum inhibitor of RNA viruses, including influenza A, B and C, now in Phase 1 testing; as well as antisense (DNA) oligomers and short, interfering RNA (siRNA) molecules that target sequences in influenza virus mRNA and have shown efficacy in murine and avian models of severe influenza . There are currently no clear data on their efficacy in clinical use.
Influenza is a potentially preventable infection and vaccination is the mainstay of influenza control. This applies to all presentations of influenza. A major problem in the treatment of influenza is that most drugs have to be administered as early as possible after infection. However, clinical symptoms are greatest two to three days after infection, rendering early diagnosis extremely difficult. Moreover, there is increasing resistance which seems to be independent of clinical use of antiviral drugs. In addition, dynamic genetic changes of influenza strains further complicate treatment possibilities. Excellent surveillance and further drug development are urgently needed.
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