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LJUBLJANA, SLOVENIA – Don’t hold your breath waiting for a substantially better, more reliably effective influenza vaccine.
That was a key cautionary message provided by vaccine expert Edward A. Belongia, MD, at the annual meeting of the European Society for Paediatric Infectious Diseases.
The effectiveness of seasonal influenza vaccine varies from 10% to 60% year by year, leaving enormous room for improvement. But many obstacles exist to developing a more consistent and reliably effective version of the seasonal influenza vaccine. And the lofty goal of creating a universal vaccine is even more ambitious, although the National Institute of Allergy and Infectious Diseases has declared it to be a top priority and mapped out a strategic plan for getting there (J Infect Dis. 2018 Jul 2;218[3]:347-54).
“Ultimately the Holy Grail is a universal flu vaccine that would provide pan-A and pan-B protection that would last for more than 1 year, with protection against avian and pandemic viruses, and would work for both children and adults. We are nowhere near that. Every 5 years someone says we’re 5 years away, and then 5 years go by and we’re still 5 years away. So I’m not making any predictions on that,” said Dr. Belongia, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wisc.) Clinic Research Institute, which is part of the U.S. Influenza Vaccine Effectiveness Network.
One of the big problems in creating a more effective flu vaccine, particularly for children, is the H3N2 virus subtype. Dr. Belongia was first author of a systematic review and meta-analysis of studies of more than a dozen recent flu seasons showing that although vaccine effectiveness against H3N2 varied widely from year to year, it was consistently lower than against influenza type B and H1N1 (Lancet Infect Dis. 2016 Aug;16[8]:942-51).
And that’s especially true in children and adolescents. Notably, in the 2014-2015 U.S. flu season, vaccine effectiveness against H3N2 in children aged 6 months to 8 years was low at 23%, but shockingly lower at a mere 7% in the 9- to 17-year-olds. Whereas in the 2017-2018 season, vaccine effectiveness against H3N2 in the 9- to 17-year-olds jumped to 46% while remaining low but consistent at 22% in the younger children.
“We see a very different age pattern here for the older children compared to the younger children, and quite frankly we don’t really understand what’s doing this,” said Dr. Belongia.
What is well understood, however, is that the problematic performance of influenza vaccines when it comes to protecting against H3N2 is a complicated matter stemming from three sources: the virus itself; the current egg-based vaccine manufacturing methodology, which is now 7 decades old; and host factors.
That troublesome H3N2 virus
Antigenic evolution of the H3N2 virus occurs at a 5- to 6-fold higher rate than for influenza B virus and roughly 17-fold faster than for H1N1. That high mutation rate makes for a moving target that’s a real problem when trying to keep a vaccine current. Also, the globular head of the virus is prone to glycosylation, which enables the virus to evade immune detection.
Vaccine-related factors
It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.
“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.
Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.
Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.
Host factors
Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.
“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.
Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).
“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.
How to build a better influenza vaccine for children
“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.
“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.
Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.
And as for the much-desired universal flu vaccine?
“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.
Dr. Belongia reported having no financial conflicts regarding his presentation.
LJUBLJANA, SLOVENIA – Don’t hold your breath waiting for a substantially better, more reliably effective influenza vaccine.
That was a key cautionary message provided by vaccine expert Edward A. Belongia, MD, at the annual meeting of the European Society for Paediatric Infectious Diseases.
The effectiveness of seasonal influenza vaccine varies from 10% to 60% year by year, leaving enormous room for improvement. But many obstacles exist to developing a more consistent and reliably effective version of the seasonal influenza vaccine. And the lofty goal of creating a universal vaccine is even more ambitious, although the National Institute of Allergy and Infectious Diseases has declared it to be a top priority and mapped out a strategic plan for getting there (J Infect Dis. 2018 Jul 2;218[3]:347-54).
“Ultimately the Holy Grail is a universal flu vaccine that would provide pan-A and pan-B protection that would last for more than 1 year, with protection against avian and pandemic viruses, and would work for both children and adults. We are nowhere near that. Every 5 years someone says we’re 5 years away, and then 5 years go by and we’re still 5 years away. So I’m not making any predictions on that,” said Dr. Belongia, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wisc.) Clinic Research Institute, which is part of the U.S. Influenza Vaccine Effectiveness Network.
One of the big problems in creating a more effective flu vaccine, particularly for children, is the H3N2 virus subtype. Dr. Belongia was first author of a systematic review and meta-analysis of studies of more than a dozen recent flu seasons showing that although vaccine effectiveness against H3N2 varied widely from year to year, it was consistently lower than against influenza type B and H1N1 (Lancet Infect Dis. 2016 Aug;16[8]:942-51).
And that’s especially true in children and adolescents. Notably, in the 2014-2015 U.S. flu season, vaccine effectiveness against H3N2 in children aged 6 months to 8 years was low at 23%, but shockingly lower at a mere 7% in the 9- to 17-year-olds. Whereas in the 2017-2018 season, vaccine effectiveness against H3N2 in the 9- to 17-year-olds jumped to 46% while remaining low but consistent at 22% in the younger children.
“We see a very different age pattern here for the older children compared to the younger children, and quite frankly we don’t really understand what’s doing this,” said Dr. Belongia.
What is well understood, however, is that the problematic performance of influenza vaccines when it comes to protecting against H3N2 is a complicated matter stemming from three sources: the virus itself; the current egg-based vaccine manufacturing methodology, which is now 7 decades old; and host factors.
That troublesome H3N2 virus
Antigenic evolution of the H3N2 virus occurs at a 5- to 6-fold higher rate than for influenza B virus and roughly 17-fold faster than for H1N1. That high mutation rate makes for a moving target that’s a real problem when trying to keep a vaccine current. Also, the globular head of the virus is prone to glycosylation, which enables the virus to evade immune detection.
Vaccine-related factors
It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.
“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.
Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.
Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.
Host factors
Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.
“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.
Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).
“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.
How to build a better influenza vaccine for children
“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.
“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.
Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.
And as for the much-desired universal flu vaccine?
“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.
Dr. Belongia reported having no financial conflicts regarding his presentation.
LJUBLJANA, SLOVENIA – Don’t hold your breath waiting for a substantially better, more reliably effective influenza vaccine.
That was a key cautionary message provided by vaccine expert Edward A. Belongia, MD, at the annual meeting of the European Society for Paediatric Infectious Diseases.
The effectiveness of seasonal influenza vaccine varies from 10% to 60% year by year, leaving enormous room for improvement. But many obstacles exist to developing a more consistent and reliably effective version of the seasonal influenza vaccine. And the lofty goal of creating a universal vaccine is even more ambitious, although the National Institute of Allergy and Infectious Diseases has declared it to be a top priority and mapped out a strategic plan for getting there (J Infect Dis. 2018 Jul 2;218[3]:347-54).
“Ultimately the Holy Grail is a universal flu vaccine that would provide pan-A and pan-B protection that would last for more than 1 year, with protection against avian and pandemic viruses, and would work for both children and adults. We are nowhere near that. Every 5 years someone says we’re 5 years away, and then 5 years go by and we’re still 5 years away. So I’m not making any predictions on that,” said Dr. Belongia, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wisc.) Clinic Research Institute, which is part of the U.S. Influenza Vaccine Effectiveness Network.
One of the big problems in creating a more effective flu vaccine, particularly for children, is the H3N2 virus subtype. Dr. Belongia was first author of a systematic review and meta-analysis of studies of more than a dozen recent flu seasons showing that although vaccine effectiveness against H3N2 varied widely from year to year, it was consistently lower than against influenza type B and H1N1 (Lancet Infect Dis. 2016 Aug;16[8]:942-51).
And that’s especially true in children and adolescents. Notably, in the 2014-2015 U.S. flu season, vaccine effectiveness against H3N2 in children aged 6 months to 8 years was low at 23%, but shockingly lower at a mere 7% in the 9- to 17-year-olds. Whereas in the 2017-2018 season, vaccine effectiveness against H3N2 in the 9- to 17-year-olds jumped to 46% while remaining low but consistent at 22% in the younger children.
“We see a very different age pattern here for the older children compared to the younger children, and quite frankly we don’t really understand what’s doing this,” said Dr. Belongia.
What is well understood, however, is that the problematic performance of influenza vaccines when it comes to protecting against H3N2 is a complicated matter stemming from three sources: the virus itself; the current egg-based vaccine manufacturing methodology, which is now 7 decades old; and host factors.
That troublesome H3N2 virus
Antigenic evolution of the H3N2 virus occurs at a 5- to 6-fold higher rate than for influenza B virus and roughly 17-fold faster than for H1N1. That high mutation rate makes for a moving target that’s a real problem when trying to keep a vaccine current. Also, the globular head of the virus is prone to glycosylation, which enables the virus to evade immune detection.
Vaccine-related factors
It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.
“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.
Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.
Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.
Host factors
Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.
“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.
Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).
“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.
How to build a better influenza vaccine for children
“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.
“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.
Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.
And as for the much-desired universal flu vaccine?
“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.
Dr. Belongia reported having no financial conflicts regarding his presentation.
REPORTING FROM ESPID 2019