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Should we prevent and treat seasonal influenza and how?
Vaccine 30 (2012) 7423–7425
Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Should we prevent and treat seasonal influenza and how?
“Vaccines and infectious diseases: the facts” Have vaccines been effective down through history in fighting or preventing infectious diseases? How do seasonal influenza vaccines and antivirals fit into this picture? And are there more effective ways to persuade the public to take preventative measures against seasonal influenza infection? The history of how science has developed vaccines and antivirals should leave little doubt about the benefits they have produced for humankind. Vaccination has been around for a long time. As a controlled exposure technique, variolation started more than 1000 years ago in Asia, and by the 16th century the Chinese were already using it to fight smallpox by placing dried smallpox scabs up the nose, which caused about 2 percent mortality. By the early 18th century word of the practice had spread across the sub-continent to the Middle East and to the Ottoman Empire where Lady Mary Wortley Montagu, wife of the British ambassador to the Sublime Porte, brought the technique back to England in 1721 to inoculate her young daughter. From there to the experimentation of Edward Jenner – the “father” of modern vaccination – by the end of that century was but a logical but remarkably inventive step intellectually. Jenner’s revolutionary smallpox vaccination of 1796 threw open the door to the array of vaccinations developed thereafter to combat many of the ancient diseases that have ravaged the world down through history such as rabies, polio or measles. Fast-forward to our present day for example there are no more cases of smallpox, as the disease and the virus have been eradicated. It was officially declared disappeared from the globe by WHO in 1980: the first infectious disease to be eradicated. Could one find a better or more obvious example of how effective vaccination can be? However, not all diseases react to vaccination in the same way or with the same rhythm of eradication, observes Dr. Ab Osterhaus, head of the department of virology at Erasmus MC in Rotterdam and ESWI chair. “Globally, polio has been reduced by 99 percent but still continues to linger in Africa and the East. It is still a problem but we have done a pretty good job – though not good enough because it might still come back,” he said, adding that measles is another serious disease where there’s been a steep decrease in incidence: “We’re almost there, too, but for some reason we can’t quite get rid of it either.”
0264-410X/$ – see front matter http://dx.doi.org/10.1016/j.vaccine.2012.08.039
Memory fades As for the use of vaccines to combat seasonal influenza, this has its challenges too. One problem with flu vaccines is their level of efficacy: it is good but could be better. The other big problem is to persuade the public to use them. “We are not doing a good enough job to address the public’s fear about the safety aspects of vaccines,” Osterhaus said. Another challenge is to keep the image of the benefits of vaccination alive and fresh in the public’s memory. This is a particularly difficult thing to do when the time lapse between flu pandemics is long: memory fades about the severity and disease burden of the pandemic and the public grows complacent. For Osterhaus the time-lapse problem is twofold. First collective memory is short. But there is also the lingering problem that some people still think exposure to infections is good for challenging the immunological system. “Anyone who travels to Africa [and sees the misery that unvaccinated populations suffer] understands the folly of that idea,” he said. Yet the solution is not just the development of hard-core science: that alone cannot convey the message. The research and public health communities have to work together by identifying their stakeholder audiences and showing them what facts about intervention strategies really are. Antivirals: what is their place? This also applies to the benefits of influenza antivirals, though Osterhaus stresses that antiviral treatment is not the panacea that some segments of the population mistakenly assume it is. Antivirals should not replace vaccination, he argues. “Antiviral treatment should be largely limited to situations where influenza type A or B is circulating, when a person belongs to a risk group, has the first symptoms of flu-like illness and can start treatment early,” he says. Thus, vaccination is still the cornerstone, but antivirals can play an important role as an adjunct in combating seasonal as well as pandemic influenza. However, he cautions that the timing of the administration of antivirals is an important factor in determining whether to use them or not. “If you cannot start within 48 hours after the onset in a patient with a well functioning immune system, they do not work.
7424
Should we prevent and treat seasonal influenza and how? / Vaccine 30 (2012) 7423–7425
On the other hand, if you have a patient with severe illness, are you going to wait 24 hours to get the full diagnosis before treating? Since antivirals have few side-effects, I think one should not hesitate in administering it in such circumstances. You can always stop 24 hours later if the symptoms prove not to be caused by influenza,” he said. “Vaccines and antivirals: the manufacturers’ perspective” Like any medicine they see on display, consumers take the availability of flu vaccines and antivirals for granted. But behind delivery to pharmacies and healthcare workers there is a complicated chain of coordination and production. Influenza vaccines prevent or mitigate infections, explains Dr. Stijn Hollemeersch, Worldwide Medical Affairs at GSK Biologicals. Vaccines are designed to induce a protective immune response in the body against the viruses represented in the vaccine. When vaccinated, the immune system of the body produces a specific response, consisting of specific antibodies that fight off the infection when exposure to the virus occurs at a later stage. Antivirals, however, are drugs that directly interfere with the replication of influenza viruses in the body and consequently their activity is limited to the period that they are administered. There are two classes of antiviral compounds against influenza viruses: M2 inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir). The first class is effective against influenza A viruses only, and widespread resistance limits their use. The neuraminidase inhibitors (NAIs) are effective against influenza A and B viruses, and resistance is less of a problem for this newer class of products; although resistance profiles differ between the two NAIs with resistance ranging from isolated cases to widespread impact having been observed. These products have a clinically acceptable safety profile. Consequently, antivirals had an important role to play in the 2009 pandemic. Their use in the treatment of seasonal influenza varies throughout the world. “The use of antivirals, however, should never detract from efforts to ensure that all eligible people receive vaccination,” Dr. Hollemeersch stresses. The logistics of vaccine production: just-in-time . . . but not easy Good surveillance data are essential if we want to make the right vaccines. Each year, based on the epidemiology of the circulating strains, WHO indicates in February what virus strains should be in the next vaccine for the Northern hemisphere. As H1N1, H3N2 and type B influenza are responsible for human seasonal influenza, recommendations are made on what representatives of these virus types and subtypes to include in the vaccine composition. Influenza viruses evolve constantly but a distinction must be made between the minor mutations, called “drift” which account for new seasonal flu strains to emerge each year versus antigenic “shift” where viruses from different hosts such as humans and pigs mix to produce entirely new strains with pandemic potential. For vaccines, the surface proteins play an important role in building up immunity to the virus and this is what vaccine manufacturers focus on. The annual process to make a seasonal influenza vaccine targeted against the strains most likely to cause disease in the next winter is a race against time, says Stijn Hollemeersch. “We have to start from scratch every year in February to make a new vaccine as per the WHO recommendations for the next winter season in the Northern hemisphere,” he said. It is a delicate process whose first six steps encompass the following: • inoculation of chicken eggs, incubation and inspection; • harvesting and separation;
• • • •
ultrafiltration; ultra-centrifugation; filtration and inactivation; diafiltration and sterile filtration.
Numerous quality checks occur at each level of production and if any of these tests fail, the whole vaccine batch fails and must be started again from the inoculation of the hen’s eggs. In parallel, some regulatory agencies require renewal clinical trials to be performed to update the vaccine license for the new formulation. If we want the vaccine to reach the vaccinees in time, the production must be finished by July because the new flu season begins soon thereafter. “Thus, we have a window of only a few weeks to fill millions of vials and syringes at the end of the production runs,” Dr. Hollemeersch said. One could ask why a universal vaccine is not manufactured to avoid the yearly race against the clock, but that still remains an elusive goal. As Hollemeersch observes: “This is the magic bullet we’ve all dreamed about for more than 20 years. While science is making progress I don’t think you’ll see a universal vaccine soon.” In the meantime, he said manufacturers continue to research how to improve their vaccines. Logistical nightmare Indeed, current vaccine production from eggs is a logistical nightmare, confirms Marc Van Ranst, Belgium’s Flu Commissioner and a leading virologist at the University of Leuven (KUL). Pointing to huge differences in vaccine distribution across the world, he said that in the best case, production meets only about 6 percent of the world population after six months, and only 18 percent of the global population after 12 months of effort. Referring to the 2009 H1N1 pandemic vaccine, he said seasonal vaccine production will influence any pandemic effort. “We saw the results of what was planned [for the 2009 event] versus what was actually produced – and the results were disappointing,” he observed. Another complicating factor is that industry uses the previous seasonal influenza peak period to extrapolate predictions for their production in the following year. According to Van Ranst, manufacturers are “perennially disappointed” that they do not make their sales targets. “They should use a rolling five-year average instead. In Belgium, this rises by about 5 percent each year. If more companies would have done that, they wouldn’t have been disappointed,” he said.
‘‘Seasonal flu vaccination and school children: The Japanese experience’’ Japan has had a checkered policy on vaccinating young students against seasonal influenza. Dr Masato Tashiro of the department of viral diseases and vaccine control within Japan’s National Institute of Infectious Disease (and WHO’s collaborating centre for influenza in the country) explained Tokyo’s view about the subject and its more recent policy choices and results. Noting that mandatory universal vaccination for all school children aged 6–15 first went into effect in 1962, Tashiro said it was based on three assumptions, namely that: young children were most susceptible to influenza virus infections especially in crowded school conditions; infected schoolchildren disseminate influenza into the community; and vaccination of schoolchildren would control influenza epidemics across the community. Unfortunately, a slow build-up of negative press coverage, based on lambasting the policy as a violation of children’s rights, finally led to a revocation of the policy in 1988.
Should we prevent and treat seasonal influenza and how? / Vaccine 30 (2012) 7423–7425
“At that point our universal vaccination programme for children was suspended and four manufactures resigned from flu vaccine production,” he said. “We did manage to later amend the law in 1994 to include vaccine recommendation for the elderly above 65 years and those with underlying chronic medical conditions.” The milestone that flipped public opinion back in favour of wider vaccination came with the 1997 outbreak in Hong Kong of the H3N2 virus. “This caused relatively severe outbreaks in our nursing homes, prompting the media to accuse the government for having no flu vaccination programme in Japan!” he said, adding that one of the lessons learned “was that pandemic vaccine policy is impossible without implementation of a seasonal vaccination programme.” Immediately thereafter a new influenza immunization programme went into effect. This was founded on the following guidelines: • it would rely on voluntary vaccination;
7425
• the elderly would be the primary immunization target, with fees covered in part by local governments; • the flu vaccine would be open to anyone, including children, but at their own expense. The vaccination trends and their positive effects took off immediately after the new programme. For example, voluntary vaccination among children rose from a base of nearly zero in 1997 to around 25 million vaccine doses administered in 2003, while excessive deaths per 100,000 young children fell from three to virtually zero over the same period. According to Tashiro, coverage in the elderly since then has reached 60 percent while excess mortality having decreased accordingly. However, he said the direct effect of flu vaccination of the elderly should be evaluated carefully “because the use of antivirals such as oseltamivir has increased remarkably in Japan at the same time.”
Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Should we prevent and treat seasonal influenza and how?
“Vaccines and infectious diseases: the facts” Have vaccines been effective down through history in fighting or preventing infectious diseases? How do seasonal influenza vaccines and antivirals fit into this picture? And are there more effective ways to persuade the public to take preventative measures against seasonal influenza infection? The history of how science has developed vaccines and antivirals should leave little doubt about the benefits they have produced for humankind. Vaccination has been around for a long time. As a controlled exposure technique, variolation started more than 1000 years ago in Asia, and by the 16th century the Chinese were already using it to fight smallpox by placing dried smallpox scabs up the nose, which caused about 2 percent mortality. By the early 18th century word of the practice had spread across the sub-continent to the Middle East and to the Ottoman Empire where Lady Mary Wortley Montagu, wife of the British ambassador to the Sublime Porte, brought the technique back to England in 1721 to inoculate her young daughter. From there to the experimentation of Edward Jenner – the “father” of modern vaccination – by the end of that century was but a logical but remarkably inventive step intellectually. Jenner’s revolutionary smallpox vaccination of 1796 threw open the door to the array of vaccinations developed thereafter to combat many of the ancient diseases that have ravaged the world down through history such as rabies, polio or measles. Fast-forward to our present day for example there are no more cases of smallpox, as the disease and the virus have been eradicated. It was officially declared disappeared from the globe by WHO in 1980: the first infectious disease to be eradicated. Could one find a better or more obvious example of how effective vaccination can be? However, not all diseases react to vaccination in the same way or with the same rhythm of eradication, observes Dr. Ab Osterhaus, head of the department of virology at Erasmus MC in Rotterdam and ESWI chair. “Globally, polio has been reduced by 99 percent but still continues to linger in Africa and the East. It is still a problem but we have done a pretty good job – though not good enough because it might still come back,” he said, adding that measles is another serious disease where there’s been a steep decrease in incidence: “We’re almost there, too, but for some reason we can’t quite get rid of it either.”
0264-410X/$ – see front matter http://dx.doi.org/10.1016/j.vaccine.2012.08.039
Memory fades As for the use of vaccines to combat seasonal influenza, this has its challenges too. One problem with flu vaccines is their level of efficacy: it is good but could be better. The other big problem is to persuade the public to use them. “We are not doing a good enough job to address the public’s fear about the safety aspects of vaccines,” Osterhaus said. Another challenge is to keep the image of the benefits of vaccination alive and fresh in the public’s memory. This is a particularly difficult thing to do when the time lapse between flu pandemics is long: memory fades about the severity and disease burden of the pandemic and the public grows complacent. For Osterhaus the time-lapse problem is twofold. First collective memory is short. But there is also the lingering problem that some people still think exposure to infections is good for challenging the immunological system. “Anyone who travels to Africa [and sees the misery that unvaccinated populations suffer] understands the folly of that idea,” he said. Yet the solution is not just the development of hard-core science: that alone cannot convey the message. The research and public health communities have to work together by identifying their stakeholder audiences and showing them what facts about intervention strategies really are. Antivirals: what is their place? This also applies to the benefits of influenza antivirals, though Osterhaus stresses that antiviral treatment is not the panacea that some segments of the population mistakenly assume it is. Antivirals should not replace vaccination, he argues. “Antiviral treatment should be largely limited to situations where influenza type A or B is circulating, when a person belongs to a risk group, has the first symptoms of flu-like illness and can start treatment early,” he says. Thus, vaccination is still the cornerstone, but antivirals can play an important role as an adjunct in combating seasonal as well as pandemic influenza. However, he cautions that the timing of the administration of antivirals is an important factor in determining whether to use them or not. “If you cannot start within 48 hours after the onset in a patient with a well functioning immune system, they do not work.
7424
Should we prevent and treat seasonal influenza and how? / Vaccine 30 (2012) 7423–7425
On the other hand, if you have a patient with severe illness, are you going to wait 24 hours to get the full diagnosis before treating? Since antivirals have few side-effects, I think one should not hesitate in administering it in such circumstances. You can always stop 24 hours later if the symptoms prove not to be caused by influenza,” he said. “Vaccines and antivirals: the manufacturers’ perspective” Like any medicine they see on display, consumers take the availability of flu vaccines and antivirals for granted. But behind delivery to pharmacies and healthcare workers there is a complicated chain of coordination and production. Influenza vaccines prevent or mitigate infections, explains Dr. Stijn Hollemeersch, Worldwide Medical Affairs at GSK Biologicals. Vaccines are designed to induce a protective immune response in the body against the viruses represented in the vaccine. When vaccinated, the immune system of the body produces a specific response, consisting of specific antibodies that fight off the infection when exposure to the virus occurs at a later stage. Antivirals, however, are drugs that directly interfere with the replication of influenza viruses in the body and consequently their activity is limited to the period that they are administered. There are two classes of antiviral compounds against influenza viruses: M2 inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir). The first class is effective against influenza A viruses only, and widespread resistance limits their use. The neuraminidase inhibitors (NAIs) are effective against influenza A and B viruses, and resistance is less of a problem for this newer class of products; although resistance profiles differ between the two NAIs with resistance ranging from isolated cases to widespread impact having been observed. These products have a clinically acceptable safety profile. Consequently, antivirals had an important role to play in the 2009 pandemic. Their use in the treatment of seasonal influenza varies throughout the world. “The use of antivirals, however, should never detract from efforts to ensure that all eligible people receive vaccination,” Dr. Hollemeersch stresses. The logistics of vaccine production: just-in-time . . . but not easy Good surveillance data are essential if we want to make the right vaccines. Each year, based on the epidemiology of the circulating strains, WHO indicates in February what virus strains should be in the next vaccine for the Northern hemisphere. As H1N1, H3N2 and type B influenza are responsible for human seasonal influenza, recommendations are made on what representatives of these virus types and subtypes to include in the vaccine composition. Influenza viruses evolve constantly but a distinction must be made between the minor mutations, called “drift” which account for new seasonal flu strains to emerge each year versus antigenic “shift” where viruses from different hosts such as humans and pigs mix to produce entirely new strains with pandemic potential. For vaccines, the surface proteins play an important role in building up immunity to the virus and this is what vaccine manufacturers focus on. The annual process to make a seasonal influenza vaccine targeted against the strains most likely to cause disease in the next winter is a race against time, says Stijn Hollemeersch. “We have to start from scratch every year in February to make a new vaccine as per the WHO recommendations for the next winter season in the Northern hemisphere,” he said. It is a delicate process whose first six steps encompass the following: • inoculation of chicken eggs, incubation and inspection; • harvesting and separation;
• • • •
ultrafiltration; ultra-centrifugation; filtration and inactivation; diafiltration and sterile filtration.
Numerous quality checks occur at each level of production and if any of these tests fail, the whole vaccine batch fails and must be started again from the inoculation of the hen’s eggs. In parallel, some regulatory agencies require renewal clinical trials to be performed to update the vaccine license for the new formulation. If we want the vaccine to reach the vaccinees in time, the production must be finished by July because the new flu season begins soon thereafter. “Thus, we have a window of only a few weeks to fill millions of vials and syringes at the end of the production runs,” Dr. Hollemeersch said. One could ask why a universal vaccine is not manufactured to avoid the yearly race against the clock, but that still remains an elusive goal. As Hollemeersch observes: “This is the magic bullet we’ve all dreamed about for more than 20 years. While science is making progress I don’t think you’ll see a universal vaccine soon.” In the meantime, he said manufacturers continue to research how to improve their vaccines. Logistical nightmare Indeed, current vaccine production from eggs is a logistical nightmare, confirms Marc Van Ranst, Belgium’s Flu Commissioner and a leading virologist at the University of Leuven (KUL). Pointing to huge differences in vaccine distribution across the world, he said that in the best case, production meets only about 6 percent of the world population after six months, and only 18 percent of the global population after 12 months of effort. Referring to the 2009 H1N1 pandemic vaccine, he said seasonal vaccine production will influence any pandemic effort. “We saw the results of what was planned [for the 2009 event] versus what was actually produced – and the results were disappointing,” he observed. Another complicating factor is that industry uses the previous seasonal influenza peak period to extrapolate predictions for their production in the following year. According to Van Ranst, manufacturers are “perennially disappointed” that they do not make their sales targets. “They should use a rolling five-year average instead. In Belgium, this rises by about 5 percent each year. If more companies would have done that, they wouldn’t have been disappointed,” he said.
‘‘Seasonal flu vaccination and school children: The Japanese experience’’ Japan has had a checkered policy on vaccinating young students against seasonal influenza. Dr Masato Tashiro of the department of viral diseases and vaccine control within Japan’s National Institute of Infectious Disease (and WHO’s collaborating centre for influenza in the country) explained Tokyo’s view about the subject and its more recent policy choices and results. Noting that mandatory universal vaccination for all school children aged 6–15 first went into effect in 1962, Tashiro said it was based on three assumptions, namely that: young children were most susceptible to influenza virus infections especially in crowded school conditions; infected schoolchildren disseminate influenza into the community; and vaccination of schoolchildren would control influenza epidemics across the community. Unfortunately, a slow build-up of negative press coverage, based on lambasting the policy as a violation of children’s rights, finally led to a revocation of the policy in 1988.
Should we prevent and treat seasonal influenza and how? / Vaccine 30 (2012) 7423–7425
“At that point our universal vaccination programme for children was suspended and four manufactures resigned from flu vaccine production,” he said. “We did manage to later amend the law in 1994 to include vaccine recommendation for the elderly above 65 years and those with underlying chronic medical conditions.” The milestone that flipped public opinion back in favour of wider vaccination came with the 1997 outbreak in Hong Kong of the H3N2 virus. “This caused relatively severe outbreaks in our nursing homes, prompting the media to accuse the government for having no flu vaccination programme in Japan!” he said, adding that one of the lessons learned “was that pandemic vaccine policy is impossible without implementation of a seasonal vaccination programme.” Immediately thereafter a new influenza immunization programme went into effect. This was founded on the following guidelines: • it would rely on voluntary vaccination;
7425
• the elderly would be the primary immunization target, with fees covered in part by local governments; • the flu vaccine would be open to anyone, including children, but at their own expense. The vaccination trends and their positive effects took off immediately after the new programme. For example, voluntary vaccination among children rose from a base of nearly zero in 1997 to around 25 million vaccine doses administered in 2003, while excessive deaths per 100,000 young children fell from three to virtually zero over the same period. According to Tashiro, coverage in the elderly since then has reached 60 percent while excess mortality having decreased accordingly. However, he said the direct effect of flu vaccination of the elderly should be evaluated carefully “because the use of antivirals such as oseltamivir has increased remarkably in Japan at the same time.”