Commentary by John G. Bartlett, MD
John G. Bartlett, MD
Editor's Note: The past week's news stories on H1N1 influenza focused on the debate about the use of adjuvants in flu vaccines, reports on viral mutations and oseltamivir resistance, the added protection from previous seasonal flu illness or vaccination, an upswing in pneumococcal disease with H1N1, risk factors for children, and a new vaccine plant for the United States. We provide links to those stories and commentary by infectious diseases expert, John G. Bartlett, MD. For more information on 2009 H1N1, see our H1N1 Influenza A (Swine Flu) Alert Center, where you will find the latest news, expert commentaries, resources for clinicians, and peer-to-peer discussions.
Did US Make a Mistake in Leaving Adjuvants out of H1N1 Vaccines?
Adjuvants are additives with immunostimulatory properties, capable of inducing more rapid seroprotection and longer-lasting immunity. Adjuvants are widely used in European and Canadian flu vaccines, but no new adjuvants have been approved for use in the United States.
Commentary. The use of adjuvant in the H1N1 vaccine would have reduced the antigenic dose and helped solve the supply problem. It was known early in the vaccine development process that the seed strain did not grow well in eggs and rapid production with timely delivery would be a challenge. The "adjuvant decision" was presumably based on 3 assumptions:
That simultaneous vaccine production and clinical trials of safety and efficacy could be accomplished. The clinical trials under the National Institute of Allergy and Infectious Diseases that confirmed safety and efficacy were completed on time.
An assumption that the 5 commercial suppliers could deliver vaccine products according to projections failed for the reasons noted above.
There was concern that the addition of adjuvant would add to the public fear about vaccine safety. We now know that more than 50% of the US public have concerns about the H1N1 vaccine despite the fact that it is manufactured similar to every influenza vaccine for the past 40 years.
Adding adjuvant to the vaccine should not be an issue in terms of product safety because the same adjuvants are used in many routine US vaccines and are also used in the H1N1 vaccines distributed in Canada and England. The issue here is that the public perception of safety with adjuvant is unknown.
What can you tell patients who express frustration that they cannot get the vaccine or anger that they got H1N1 flu because of the vaccine supply deficit? Tell them that there was an assumption that timelines from commercial suppliers would be met and that there was concern that the addition of adjuvant would decrease public acceptance because of safety concerns. In retrospect, it might have been better to have made at least part of the supply of H1N1 vaccine with adjuvant.
Norway Finds H1N1 Mutation in Flu Fatalities
A potentially significant mutation in the H1N1 influenza strain was found in 2 people who died of complications from the virus and in a third person who was seriously ill with influenza. Norwegian health authorities fear that the mutation might enhance the virus' ability to infect the lower respiratory tract.
Commentary. Influenza viruses are expected to mutate. Concern arises when the mutation has clinical consequences in 4 categories:
Resistance to oseltamivir and/or zanamivir. So far, the World Health Organization (WHO) has reported a total of 52 strains of 2009 H1N1 that are resistant to oseltamivir, including 15 in the United States. All of these have been the 274Y codon mutation that confers resistance to oseltamivir but not zanamivir. No strain has proven resistant to zanamivir.
Increased infectivity: 2009 H1N1 already has this property.
Increased virulence: This is the concern expressed in the report from Norway. The implication is that a mutational change could alter pathogenic potential, presumably by its direct effect on the lower respiratory tract where it incites "cytokine storm." Increased virulence is of concern because the mutation was found in 3 serious cases, but analysis of subsequent serious cases did not show the mutation. The association is far from established.
Mutational change sufficient to alter vaccine protection. Mutational change would be compared with the seed strain used to produce the vaccine, and studies to date have shown this change only in a single isolate.
Tell patients who are concerned about viral mutation that this information is being systemically collected, and so far it shows that the vaccine is still effective; oseltamivir is effective against > 99% of strains; and there is no convincing evidence of increased virulence.
Seasonal Flu Vaccine May Cut Swine Flu Risk
A study in military personnel found that people who received a seasonal influenza vaccine last year are at lower risk for H1N1 influenza or serious disease if they do acquire H1N1 infection. However, protection from the seasonal flu vaccine did not appear to be effective for persons aged 25-39 years.
Commentary. A recent publication[1] provides an extraordinarily important observation that may explain why we are seeing a pandemic with a high attack rate and a low mortality rate. It also explains the interesting age distribution in this pandemic. The presumed mechanism is that repeated exposures to different H1N1 antigens by infection or vaccination do not elicit protection from infection through humoral immunity (antibody response), but there is reduced severity of disease because of memory T-cell response that has not been previously measured.
Pre-existing Immunity Against Swine-Origin H1N1 Influenza Viruses in the General Human Population[1]
The 2009 influenza A (H1N1) strain has caused enough infections to be considered a WHO-defined pandemic, but the clinical severity so far is similar to seasonal flu. Neutralizing antibodies to this new strain are found almost exclusively in persons born before 1957; therefore, how do we explain the relatively benign course in most persons under 52 years of age? To answer this question, investigators examined the molecular basis of immunity to this new strain. They found a relatively poor B-cell response with antibody production (the standard method of measuring immunity to influenza viruses). Instead, they found antigen recognition and response in memory T cells. This response was similar to that seen with seasonal influenza. The investigators concluded that the lack of B-cell recognition explains the high attack rate especially in young persons, but the memory cell recognition explains the lower severity than that which might be expected with a pandemic.
Commentary. This appears to be a major advance in understanding the dynamics of this influenza epidemic -- too many cases to count, but a total mortality of about 4000 -- with first and second waves that affected primarily young people. In contrast, the average mortality for seasonal flu in the United States is 36,000/year, and most of the deaths are in the very young and very old. This study provides a plausible explanation for these unusual epidemiologic observations. The scientific explanation doesn't really change the recommendations about management because the clinical impact preceded the science.
You can tell your patients that the more times they have had influenza or influenza vaccine, the less likely they are to contract 2009 influenza A (H1N1).
CDC Warns of Increasing Pneumococcal Disease Associated With H1N1 Flu
Rates of serious pneumococcal infections associated with H1N1 influenza are increasing around the country. Surveillance in the Denver, Colorado, metropolitan area finds that the number of cases of invasive pneumococcal disease has tripled compared with the 5-year average, affecting mostly adults under the age of 60 years.
Commentary. The frequent association between Streptococcus pneumoniae superinfection in patients with viral respiratory tract infections has been well established for decades, and is presumably a result of dysfunctional alveolar macrophages. The classic presentation with influenza is typical flu symptoms followed by improvement, and then deterioration as a result of pneumococcal pneumonia.[2] This association was also emphasized in the retrospective analysis of 8398 lethal cases of influenza in the 1918-1919 pandemic when S pneumoniae was the major lethal pathogen.[3] The association was emphasized again in the US Centers for Disease Control and Prevention (CDC) review of tissue specimens in 77 lethal cases from the current 2009 (H1N1) pandemic, which showed 22 cases of bacterial pneumonia with the pneumococcus as the dominant strain.[4]
What does this mean for practitioners?
When should you suspect pneumococcal superinfection with confirmed or suspected infection with pandemic 2009 influenza A (H1N1)? The following course of action includes:
Clinical and laboratory clues A course characterized by clinical improvement, then deterioration. (Note that not all patients have this biphasic course)
Lab clues often show S pneumoniae by sputum Gram stain, culture of blood, or sputum or urinary antigen; elevated white blood cell count with shift (uncommon with uncomplicated influenza); and imaging showing focal consolidation
Diagnosis: Physicians are urged to establish this diagnosis with cultures of sputum, blood, and urinary antigen tests
Treatment: The preferred drugs for pneumococcal pneumonia in 2009-2010 are the beta-lactams. More than 95% of strains are sensitive to penicillin G, amoxicillin, ceftriaxone, cefotaxime, etc. Macrolides are inferior for this infection. Fluoroquinolones are virtually always active. Vancomycin and linezolid are also active but used only when there is concern for methicillin-resistant Staphylococcus aureus (MRSA)
Prevention: This association emphasizes the potential utility of pneumococcal vaccine polyvalent (Pneumovax®) in adults with CDC-defined risks and pneumococcal 7-valent conjugate vaccine (Prevnar®) in children. The data on efficacy of pneumococcal 7-valent conjugate vaccine in children are simply amazing -- not only for the children who get it, but for the herd immunity impact that protects adults as well.[5] The benefit of pneumococcal vaccine polyvalent in adults is far less striking, and it seems better at preventing pneumococcal bacteremia than pneumococcal pneumonia.[6]
WHO Probing Drug Resistant H1N1 Flu in Britain and U.S.
WHO is looking into reports in the United Kingdom and the United States that the H1N1 influenza virus may have developed resistance to oseltamivir. In Wales, oseltamivir-resistant H1N1 has been confirmed in 5 patients who had severely compromised immune systems. Four similar cases have been identified at Duke University, Durham, North Carolina.
Commentary. The frequency of oseltamivir resistance is very low. Data from isolates collected by WHO indicate just 52 resistant strains; the data for the United States for September 1-November 14, 2009 showed resistance to oseltamivir in 10 of 1209 (0.8%). No one has detected a zanamivir-resistant strain. The unique feature of this case is that it apparently represents transmitted resistance because this patient had no prior exposure to oseltamivir. In the United States, 1 patient with oseltamivir resistance without exposure to the drug for either treatment or prophylaxis has been identified.[7]
What clinicians need to know:
Oseltamivir is active against > 99% of strains of 2009 influenza A (H1N1) and remains the preferred drug;
This could change rapidly as it did with seasonal flu and H1N1 last season when 99% of strains became resistant, but there has been little evidence so far that the pandemic strain of H1N1 will do this;
The low level of oseltamivir resistance noted through November 14, 2009 is expected, and nearly all cases involving resistant strains in the United States have been associated with documented oseltamivir exposure for treatment or prophylaxis; and
Zanamivir continues to be active against all tested strains of 2009 (H1N1), but the delivery system is somewhat complicated, and chronic lung disease and asthma are contraindications to its use.
Risk Factors and Outcomes Among Children Admitted to the Hospital With Pandemic H1N1 Influenza[8]
Investigators reviewed 58 cases of pandemic H1N1 influenza in hospitalized children in Ontario, Canada, from May 8 to July 22, 2009. These cases were compared with 200 cases in children with seasonal flu admitted to the hospital during the 5 previous years. The results showed that in more children with pandemic H1N1 influenza, asthma was the underlying condition (13/58 [22%] vs 11/200 [6%]; P < .001), and more children admitted to the intensive care unit required mechanical ventilation (5/12 [42%] vs 2/28 [7%]; P = .02). The conclusion is that the current pandemic of H1N1 is different from seasonal flu in terms of the risk associated with asthma and severity of disease in children. Commentary. The message for pediatricians and others who care for children: Children with asthma should be a high priority for H1N1 pandemic flu vaccine and preemptive antiviral treatment; The injected vaccine is considered safe in children and adults with asthma; These children should not receive the live virus vaccine; The investigators noted that other reports also implicate asthma as an associated or predisposing condition in 21%-30% of hospitalized patients during this pandemic, so this report is not an outlier; and The risk in the report from Canada did not appear to be related to the severity of asthma. In other words, mild asthma is as big a risk as serious asthma. Next-Generation Flu Vaccine Plant to Open in the United States[9]
Novartis Pharmaceuticals Corporation plans to open a flu vaccine plant in Holly Hill, North Carolina, in 2011. The plant will use cell-based cultures of influenza virus, have a production capacity of 50 million doses of seasonal flu vaccine, and up to 150 million doses of pandemic vaccine within 6 months. The inoculum will be 3.75 mg antigen with adjuvant.
Commentary. This will be the only flu vaccine produced in the United States. Local production is important because severe pandemics or bioterrorism events are likely to put pressure on companies that produce vaccines to preferentially serve nationalistic needs rather than honor contracts with distant countries. Also, the plant will use cell-based cultures to grow influenza virus rather than eggs, which is the standard for all contemporary flu vaccines. This will result in a reduction in egg dependency and faster production. Vaccine authorities have talked about the need for cell-based vaccines for 10 years.
John G. Bartlett, MD
Editor's Note: The past week's news stories on H1N1 influenza focused on the debate about the use of adjuvants in flu vaccines, reports on viral mutations and oseltamivir resistance, the added protection from previous seasonal flu illness or vaccination, an upswing in pneumococcal disease with H1N1, risk factors for children, and a new vaccine plant for the United States. We provide links to those stories and commentary by infectious diseases expert, John G. Bartlett, MD. For more information on 2009 H1N1, see our H1N1 Influenza A (Swine Flu) Alert Center, where you will find the latest news, expert commentaries, resources for clinicians, and peer-to-peer discussions.
Did US Make a Mistake in Leaving Adjuvants out of H1N1 Vaccines?
Adjuvants are additives with immunostimulatory properties, capable of inducing more rapid seroprotection and longer-lasting immunity. Adjuvants are widely used in European and Canadian flu vaccines, but no new adjuvants have been approved for use in the United States.
Commentary. The use of adjuvant in the H1N1 vaccine would have reduced the antigenic dose and helped solve the supply problem. It was known early in the vaccine development process that the seed strain did not grow well in eggs and rapid production with timely delivery would be a challenge. The "adjuvant decision" was presumably based on 3 assumptions:
That simultaneous vaccine production and clinical trials of safety and efficacy could be accomplished. The clinical trials under the National Institute of Allergy and Infectious Diseases that confirmed safety and efficacy were completed on time.
An assumption that the 5 commercial suppliers could deliver vaccine products according to projections failed for the reasons noted above.
There was concern that the addition of adjuvant would add to the public fear about vaccine safety. We now know that more than 50% of the US public have concerns about the H1N1 vaccine despite the fact that it is manufactured similar to every influenza vaccine for the past 40 years.
Adding adjuvant to the vaccine should not be an issue in terms of product safety because the same adjuvants are used in many routine US vaccines and are also used in the H1N1 vaccines distributed in Canada and England. The issue here is that the public perception of safety with adjuvant is unknown.
What can you tell patients who express frustration that they cannot get the vaccine or anger that they got H1N1 flu because of the vaccine supply deficit? Tell them that there was an assumption that timelines from commercial suppliers would be met and that there was concern that the addition of adjuvant would decrease public acceptance because of safety concerns. In retrospect, it might have been better to have made at least part of the supply of H1N1 vaccine with adjuvant.
Norway Finds H1N1 Mutation in Flu Fatalities
A potentially significant mutation in the H1N1 influenza strain was found in 2 people who died of complications from the virus and in a third person who was seriously ill with influenza. Norwegian health authorities fear that the mutation might enhance the virus' ability to infect the lower respiratory tract.
Commentary. Influenza viruses are expected to mutate. Concern arises when the mutation has clinical consequences in 4 categories:
Resistance to oseltamivir and/or zanamivir. So far, the World Health Organization (WHO) has reported a total of 52 strains of 2009 H1N1 that are resistant to oseltamivir, including 15 in the United States. All of these have been the 274Y codon mutation that confers resistance to oseltamivir but not zanamivir. No strain has proven resistant to zanamivir.
Increased infectivity: 2009 H1N1 already has this property.
Increased virulence: This is the concern expressed in the report from Norway. The implication is that a mutational change could alter pathogenic potential, presumably by its direct effect on the lower respiratory tract where it incites "cytokine storm." Increased virulence is of concern because the mutation was found in 3 serious cases, but analysis of subsequent serious cases did not show the mutation. The association is far from established.
Mutational change sufficient to alter vaccine protection. Mutational change would be compared with the seed strain used to produce the vaccine, and studies to date have shown this change only in a single isolate.
Tell patients who are concerned about viral mutation that this information is being systemically collected, and so far it shows that the vaccine is still effective; oseltamivir is effective against > 99% of strains; and there is no convincing evidence of increased virulence.
Seasonal Flu Vaccine May Cut Swine Flu Risk
A study in military personnel found that people who received a seasonal influenza vaccine last year are at lower risk for H1N1 influenza or serious disease if they do acquire H1N1 infection. However, protection from the seasonal flu vaccine did not appear to be effective for persons aged 25-39 years.
Commentary. A recent publication[1] provides an extraordinarily important observation that may explain why we are seeing a pandemic with a high attack rate and a low mortality rate. It also explains the interesting age distribution in this pandemic. The presumed mechanism is that repeated exposures to different H1N1 antigens by infection or vaccination do not elicit protection from infection through humoral immunity (antibody response), but there is reduced severity of disease because of memory T-cell response that has not been previously measured.
Pre-existing Immunity Against Swine-Origin H1N1 Influenza Viruses in the General Human Population[1]
The 2009 influenza A (H1N1) strain has caused enough infections to be considered a WHO-defined pandemic, but the clinical severity so far is similar to seasonal flu. Neutralizing antibodies to this new strain are found almost exclusively in persons born before 1957; therefore, how do we explain the relatively benign course in most persons under 52 years of age? To answer this question, investigators examined the molecular basis of immunity to this new strain. They found a relatively poor B-cell response with antibody production (the standard method of measuring immunity to influenza viruses). Instead, they found antigen recognition and response in memory T cells. This response was similar to that seen with seasonal influenza. The investigators concluded that the lack of B-cell recognition explains the high attack rate especially in young persons, but the memory cell recognition explains the lower severity than that which might be expected with a pandemic.
Commentary. This appears to be a major advance in understanding the dynamics of this influenza epidemic -- too many cases to count, but a total mortality of about 4000 -- with first and second waves that affected primarily young people. In contrast, the average mortality for seasonal flu in the United States is 36,000/year, and most of the deaths are in the very young and very old. This study provides a plausible explanation for these unusual epidemiologic observations. The scientific explanation doesn't really change the recommendations about management because the clinical impact preceded the science.
You can tell your patients that the more times they have had influenza or influenza vaccine, the less likely they are to contract 2009 influenza A (H1N1).
CDC Warns of Increasing Pneumococcal Disease Associated With H1N1 Flu
Rates of serious pneumococcal infections associated with H1N1 influenza are increasing around the country. Surveillance in the Denver, Colorado, metropolitan area finds that the number of cases of invasive pneumococcal disease has tripled compared with the 5-year average, affecting mostly adults under the age of 60 years.
Commentary. The frequent association between Streptococcus pneumoniae superinfection in patients with viral respiratory tract infections has been well established for decades, and is presumably a result of dysfunctional alveolar macrophages. The classic presentation with influenza is typical flu symptoms followed by improvement, and then deterioration as a result of pneumococcal pneumonia.[2] This association was also emphasized in the retrospective analysis of 8398 lethal cases of influenza in the 1918-1919 pandemic when S pneumoniae was the major lethal pathogen.[3] The association was emphasized again in the US Centers for Disease Control and Prevention (CDC) review of tissue specimens in 77 lethal cases from the current 2009 (H1N1) pandemic, which showed 22 cases of bacterial pneumonia with the pneumococcus as the dominant strain.[4]
What does this mean for practitioners?
When should you suspect pneumococcal superinfection with confirmed or suspected infection with pandemic 2009 influenza A (H1N1)? The following course of action includes:
Clinical and laboratory clues A course characterized by clinical improvement, then deterioration. (Note that not all patients have this biphasic course)
Lab clues often show S pneumoniae by sputum Gram stain, culture of blood, or sputum or urinary antigen; elevated white blood cell count with shift (uncommon with uncomplicated influenza); and imaging showing focal consolidation
Diagnosis: Physicians are urged to establish this diagnosis with cultures of sputum, blood, and urinary antigen tests
Treatment: The preferred drugs for pneumococcal pneumonia in 2009-2010 are the beta-lactams. More than 95% of strains are sensitive to penicillin G, amoxicillin, ceftriaxone, cefotaxime, etc. Macrolides are inferior for this infection. Fluoroquinolones are virtually always active. Vancomycin and linezolid are also active but used only when there is concern for methicillin-resistant Staphylococcus aureus (MRSA)
Prevention: This association emphasizes the potential utility of pneumococcal vaccine polyvalent (Pneumovax®) in adults with CDC-defined risks and pneumococcal 7-valent conjugate vaccine (Prevnar®) in children. The data on efficacy of pneumococcal 7-valent conjugate vaccine in children are simply amazing -- not only for the children who get it, but for the herd immunity impact that protects adults as well.[5] The benefit of pneumococcal vaccine polyvalent in adults is far less striking, and it seems better at preventing pneumococcal bacteremia than pneumococcal pneumonia.[6]
WHO Probing Drug Resistant H1N1 Flu in Britain and U.S.
WHO is looking into reports in the United Kingdom and the United States that the H1N1 influenza virus may have developed resistance to oseltamivir. In Wales, oseltamivir-resistant H1N1 has been confirmed in 5 patients who had severely compromised immune systems. Four similar cases have been identified at Duke University, Durham, North Carolina.
Commentary. The frequency of oseltamivir resistance is very low. Data from isolates collected by WHO indicate just 52 resistant strains; the data for the United States for September 1-November 14, 2009 showed resistance to oseltamivir in 10 of 1209 (0.8%). No one has detected a zanamivir-resistant strain. The unique feature of this case is that it apparently represents transmitted resistance because this patient had no prior exposure to oseltamivir. In the United States, 1 patient with oseltamivir resistance without exposure to the drug for either treatment or prophylaxis has been identified.[7]
What clinicians need to know:
Oseltamivir is active against > 99% of strains of 2009 influenza A (H1N1) and remains the preferred drug;
This could change rapidly as it did with seasonal flu and H1N1 last season when 99% of strains became resistant, but there has been little evidence so far that the pandemic strain of H1N1 will do this;
The low level of oseltamivir resistance noted through November 14, 2009 is expected, and nearly all cases involving resistant strains in the United States have been associated with documented oseltamivir exposure for treatment or prophylaxis; and
Zanamivir continues to be active against all tested strains of 2009 (H1N1), but the delivery system is somewhat complicated, and chronic lung disease and asthma are contraindications to its use.
Risk Factors and Outcomes Among Children Admitted to the Hospital With Pandemic H1N1 Influenza[8]
Investigators reviewed 58 cases of pandemic H1N1 influenza in hospitalized children in Ontario, Canada, from May 8 to July 22, 2009. These cases were compared with 200 cases in children with seasonal flu admitted to the hospital during the 5 previous years. The results showed that in more children with pandemic H1N1 influenza, asthma was the underlying condition (13/58 [22%] vs 11/200 [6%]; P < .001), and more children admitted to the intensive care unit required mechanical ventilation (5/12 [42%] vs 2/28 [7%]; P = .02). The conclusion is that the current pandemic of H1N1 is different from seasonal flu in terms of the risk associated with asthma and severity of disease in children. Commentary. The message for pediatricians and others who care for children: Children with asthma should be a high priority for H1N1 pandemic flu vaccine and preemptive antiviral treatment; The injected vaccine is considered safe in children and adults with asthma; These children should not receive the live virus vaccine; The investigators noted that other reports also implicate asthma as an associated or predisposing condition in 21%-30% of hospitalized patients during this pandemic, so this report is not an outlier; and The risk in the report from Canada did not appear to be related to the severity of asthma. In other words, mild asthma is as big a risk as serious asthma. Next-Generation Flu Vaccine Plant to Open in the United States[9]
Novartis Pharmaceuticals Corporation plans to open a flu vaccine plant in Holly Hill, North Carolina, in 2011. The plant will use cell-based cultures of influenza virus, have a production capacity of 50 million doses of seasonal flu vaccine, and up to 150 million doses of pandemic vaccine within 6 months. The inoculum will be 3.75 mg antigen with adjuvant.
Commentary. This will be the only flu vaccine produced in the United States. Local production is important because severe pandemics or bioterrorism events are likely to put pressure on companies that produce vaccines to preferentially serve nationalistic needs rather than honor contracts with distant countries. Also, the plant will use cell-based cultures to grow influenza virus rather than eggs, which is the standard for all contemporary flu vaccines. This will result in a reduction in egg dependency and faster production. Vaccine authorities have talked about the need for cell-based vaccines for 10 years.
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