Low IgG1/high IgG4 ratios seen in pregnancy may alter flu vaccine response

PHILADELPHIA – Low IgG1/high IgG4 ratios appear to be more common in pregnant women and may be associated with a diminished response to influenza vaccination, according to Dr. Elizabeth P. Schlaudecker.

“Basically, we know that at the maternal-fetal interface, there are lots of cytokine changes going on and lots of immunologic changes going on, but does this immune milieu of pregnancy actually influence systemic response? Obviously we think it does, but does it really affect the pregnant woman’s response to immunization? In turn, does it really influence the magnitude and character of the antibody response to flu vaccine?” Dr. Schlaudecker, of Cincinnati Children’s Hospital Medical Center, said at an annual scientific meeting on infectious diseases.

These questions prompted her research, and the answers are important because pregnant women don’t do well during flu seasons, she said, noting that “this was especially brought to light during the H1N1 pandemic,” when pregnant women had higher rates of hospital admission, more medical encounters with confirmed or suspected influenza, and greater severity of disease during late pregnancy than nonpregnant women and others.

These effects, which also occur during regular flu seasons, are more pronounced during the second and third trimesters, she said.

Because of this, influenza vaccine is recommended universally in pregnancy with the goal of preventing infection in both mothers and infants.

To determine whether the effects of pregnancy that worsen the outcome of influenza infection also suppress the response to flu vaccine, Dr. Schlaudecker and her colleagues reviewed reports about the immunogenicity of influenza vaccine in pregnancy.

Most studies and reports show that vaccinated pregnant women are likely to have seroprotective responses, but few have compared pregnant and nonpregnant women, so she recruited 70 pregnant women and 65 nonpregnant women, aged 18-39 years, and compared sera before and 28 days after influenza immunization during the 2011-2012 and 2012-2013 flu seasons.

Hemagglutination inhibition (HAI), as expected, was reduced during pregnancy. The pregnant women, who were in either their second or third trimester, had significantly lower HAI titers for anti-influenza H3N2 (154.55 vs. 242.51), and the differences approached significance for both H1N1 (129.96 vs. 181.84) and B antigens (24.91 v. 35.20). She reported these findings at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

“So I took this information and realized that women may have a decreased antibody response when they are pregnant, and hypothesized that during this time of pregnancy, there are cytokines associated with this maternal-fetal interface that suppress the IgG1 and IgG3 response and promote an IgG4 response to influenza vaccination, particularly during the second and third trimesters, when production of these cytokines should be highest,” she said.

This matters, because the four subclasses of IgG have functional differences. The effector functions of the IgG subclasses are usually opsonization and complement activation, and activation of inflammatory cells through Fc-gamma receptors. IgG1 and IgG3 are more effective than IgG2 or IgG4 in binding stimulatory Fc-gamma receptors and activating complement, she explained.

“IgG4 is also functionally monovalent, so it doesn’t aggregate antigens very well, and it makes it less protective against viruses,” she said, explaining that in normal, nonpregnant women, IgG1 and IgG3 are the predominant responders to viral infection, and they are most likely to be involved in flu virus protection.

“So the question is, although we know [down-regulation of IgG1 and IgG3, and up-regulation of IgG4,] is taking place around the placenta, are these cytokine effects actually circulating systemically enough to affect the flu vaccine?” she asked.

In the study participants, there was a general trend for most pregnant women to have responses that had high IgG4s and low IgG1s, which is not protective, and for nonpregnant women to have high IgG1s and low IgG4s.

The difference between the groups in this regard was not statistically significant, but there were significantly more pregnant women than nonpregnant women with high IgG4 and low IgG1 (10% vs. 0%), and there were significantly fewer pregnant women than nonpregnant women with low IgG4 and high IgG1 (3% vs. 15%), she said.

Both anti-H1N1 HAI and IgG1 titers were significantly lower in pregnant vs. nonpregnant women, but for anti-H1N1 IgG4 titers, the levels were much higher in pregnant vs. nonpregnant women, she said.

“These correlated with each other, suggesting that when you have a high HAI titer, you have a high IgG1 response, which goes along with IgG1 being the predominant IgG isotype and the one most associated with protecting against viral disease,” she said.

“A subset of these women had this very high IgG4 and low IgG1 response, and this suggests a Th2/Treg influence. This unique isotype profile was not found in any nonpregnant women,” she said, adding that very few pregnant women in their second or third trimester make the high IgG1/low IgG4 that should provide a good response to flu vaccine.

Although Dr. Schlaudecker acknowledged that 80%-90% of the pregnant women in the study had protective HAI titers after immunization, she said the findings have important implications.

“I’m concerned that these low IgG1/high IgG4 ratios seen in pregnant women might actually be giving poor protection against flu infection, which brings us back to the pediatric patients. If pregnant women are not protected well, we are not protecting the babies as well. This suggests that we might need to reconsider approaches to timing of flu vaccine or actually the particular vaccines that we give to pregnant women, and it also shows that pregnancy likely effects systemic responses to things like flu vaccine and other vaccines,” she said.

Dr. Schlaudecker reported having no disclosures.

PHILADELPHIA – Low IgG1/high IgG4 ratios appear to be more common in pregnant women and may be associated with a diminished response to influenza vaccination, according to Dr. Elizabeth P. Schlaudecker.

“Basically, we know that at the maternal-fetal interface, there are lots of cytokine changes going on and lots of immunologic changes going on, but does this immune milieu of pregnancy actually influence systemic response? Obviously we think it does, but does it really affect the pregnant woman’s response to immunization? In turn, does it really influence the magnitude and character of the antibody response to flu vaccine?” Dr. Schlaudecker, of Cincinnati Children’s Hospital Medical Center, said at an annual scientific meeting on infectious diseases.

These questions prompted her research, and the answers are important because pregnant women don’t do well during flu seasons, she said, noting that “this was especially brought to light during the H1N1 pandemic,” when pregnant women had higher rates of hospital admission, more medical encounters with confirmed or suspected influenza, and greater severity of disease during late pregnancy than nonpregnant women and others.

These effects, which also occur during regular flu seasons, are more pronounced during the second and third trimesters, she said.

Because of this, influenza vaccine is recommended universally in pregnancy with the goal of preventing infection in both mothers and infants.

To determine whether the effects of pregnancy that worsen the outcome of influenza infection also suppress the response to flu vaccine, Dr. Schlaudecker and her colleagues reviewed reports about the immunogenicity of influenza vaccine in pregnancy.

Most studies and reports show that vaccinated pregnant women are likely to have seroprotective responses, but few have compared pregnant and nonpregnant women, so she recruited 70 pregnant women and 65 nonpregnant women, aged 18-39 years, and compared sera before and 28 days after influenza immunization during the 2011-2012 and 2012-2013 flu seasons.

Hemagglutination inhibition (HAI), as expected, was reduced during pregnancy. The pregnant women, who were in either their second or third trimester, had significantly lower HAI titers for anti-influenza H3N2 (154.55 vs. 242.51), and the differences approached significance for both H1N1 (129.96 vs. 181.84) and B antigens (24.91 v. 35.20). She reported these findings at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

“So I took this information and realized that women may have a decreased antibody response when they are pregnant, and hypothesized that during this time of pregnancy, there are cytokines associated with this maternal-fetal interface that suppress the IgG1 and IgG3 response and promote an IgG4 response to influenza vaccination, particularly during the second and third trimesters, when production of these cytokines should be highest,” she said.

This matters, because the four subclasses of IgG have functional differences. The effector functions of the IgG subclasses are usually opsonization and complement activation, and activation of inflammatory cells through Fc-gamma receptors. IgG1 and IgG3 are more effective than IgG2 or IgG4 in binding stimulatory Fc-gamma receptors and activating complement, she explained.

“IgG4 is also functionally monovalent, so it doesn’t aggregate antigens very well, and it makes it less protective against viruses,” she said, explaining that in normal, nonpregnant women, IgG1 and IgG3 are the predominant responders to viral infection, and they are most likely to be involved in flu virus protection.

“So the question is, although we know [down-regulation of IgG1 and IgG3, and up-regulation of IgG4,] is taking place around the placenta, are these cytokine effects actually circulating systemically enough to affect the flu vaccine?” she asked.

In the study participants, there was a general trend for most pregnant women to have responses that had high IgG4s and low IgG1s, which is not protective, and for nonpregnant women to have high IgG1s and low IgG4s.

The difference between the groups in this regard was not statistically significant, but there were significantly more pregnant women than nonpregnant women with high IgG4 and low IgG1 (10% vs. 0%), and there were significantly fewer pregnant women than nonpregnant women with low IgG4 and high IgG1 (3% vs. 15%), she said.

Both anti-H1N1 HAI and IgG1 titers were significantly lower in pregnant vs. nonpregnant women, but for anti-H1N1 IgG4 titers, the levels were much higher in pregnant vs. nonpregnant women, she said.

“These correlated with each other, suggesting that when you have a high HAI titer, you have a high IgG1 response, which goes along with IgG1 being the predominant IgG isotype and the one most associated with protecting against viral disease,” she said.

“A subset of these women had this very high IgG4 and low IgG1 response, and this suggests a Th2/Treg influence. This unique isotype profile was not found in any nonpregnant women,” she said, adding that very few pregnant women in their second or third trimester make the high IgG1/low IgG4 that should provide a good response to flu vaccine.

Although Dr. Schlaudecker acknowledged that 80%-90% of the pregnant women in the study had protective HAI titers after immunization, she said the findings have important implications.

“I’m concerned that these low IgG1/high IgG4 ratios seen in pregnant women might actually be giving poor protection against flu infection, which brings us back to the pediatric patients. If pregnant women are not protected well, we are not protecting the babies as well. This suggests that we might need to reconsider approaches to timing of flu vaccine or actually the particular vaccines that we give to pregnant women, and it also shows that pregnancy likely effects systemic responses to things like flu vaccine and other vaccines,” she said.

Dr. Schlaudecker reported having no disclosures.

PHILADELPHIA – Low IgG1/high IgG4 ratios appear to be more common in pregnant women and may be associated with a diminished response to influenza vaccination, according to Dr. Elizabeth P. Schlaudecker.

“Basically, we know that at the maternal-fetal interface, there are lots of cytokine changes going on and lots of immunologic changes going on, but does this immune milieu of pregnancy actually influence systemic response? Obviously we think it does, but does it really affect the pregnant woman’s response to immunization? In turn, does it really influence the magnitude and character of the antibody response to flu vaccine?” Dr. Schlaudecker, of Cincinnati Children’s Hospital Medical Center, said at an annual scientific meeting on infectious diseases.

These questions prompted her research, and the answers are important because pregnant women don’t do well during flu seasons, she said, noting that “this was especially brought to light during the H1N1 pandemic,” when pregnant women had higher rates of hospital admission, more medical encounters with confirmed or suspected influenza, and greater severity of disease during late pregnancy than nonpregnant women and others.

These effects, which also occur during regular flu seasons, are more pronounced during the second and third trimesters, she said.

Because of this, influenza vaccine is recommended universally in pregnancy with the goal of preventing infection in both mothers and infants.

To determine whether the effects of pregnancy that worsen the outcome of influenza infection also suppress the response to flu vaccine, Dr. Schlaudecker and her colleagues reviewed reports about the immunogenicity of influenza vaccine in pregnancy.

Most studies and reports show that vaccinated pregnant women are likely to have seroprotective responses, but few have compared pregnant and nonpregnant women, so she recruited 70 pregnant women and 65 nonpregnant women, aged 18-39 years, and compared sera before and 28 days after influenza immunization during the 2011-2012 and 2012-2013 flu seasons.

Hemagglutination inhibition (HAI), as expected, was reduced during pregnancy. The pregnant women, who were in either their second or third trimester, had significantly lower HAI titers for anti-influenza H3N2 (154.55 vs. 242.51), and the differences approached significance for both H1N1 (129.96 vs. 181.84) and B antigens (24.91 v. 35.20). She reported these findings at the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

“So I took this information and realized that women may have a decreased antibody response when they are pregnant, and hypothesized that during this time of pregnancy, there are cytokines associated with this maternal-fetal interface that suppress the IgG1 and IgG3 response and promote an IgG4 response to influenza vaccination, particularly during the second and third trimesters, when production of these cytokines should be highest,” she said.

This matters, because the four subclasses of IgG have functional differences. The effector functions of the IgG subclasses are usually opsonization and complement activation, and activation of inflammatory cells through Fc-gamma receptors. IgG1 and IgG3 are more effective than IgG2 or IgG4 in binding stimulatory Fc-gamma receptors and activating complement, she explained.

“IgG4 is also functionally monovalent, so it doesn’t aggregate antigens very well, and it makes it less protective against viruses,” she said, explaining that in normal, nonpregnant women, IgG1 and IgG3 are the predominant responders to viral infection, and they are most likely to be involved in flu virus protection.

“So the question is, although we know [down-regulation of IgG1 and IgG3, and up-regulation of IgG4,] is taking place around the placenta, are these cytokine effects actually circulating systemically enough to affect the flu vaccine?” she asked.

In the study participants, there was a general trend for most pregnant women to have responses that had high IgG4s and low IgG1s, which is not protective, and for nonpregnant women to have high IgG1s and low IgG4s.

The difference between the groups in this regard was not statistically significant, but there were significantly more pregnant women than nonpregnant women with high IgG4 and low IgG1 (10% vs. 0%), and there were significantly fewer pregnant women than nonpregnant women with low IgG4 and high IgG1 (3% vs. 15%), she said.

Both anti-H1N1 HAI and IgG1 titers were significantly lower in pregnant vs. nonpregnant women, but for anti-H1N1 IgG4 titers, the levels were much higher in pregnant vs. nonpregnant women, she said.

“These correlated with each other, suggesting that when you have a high HAI titer, you have a high IgG1 response, which goes along with IgG1 being the predominant IgG isotype and the one most associated with protecting against viral disease,” she said.

“A subset of these women had this very high IgG4 and low IgG1 response, and this suggests a Th2/Treg influence. This unique isotype profile was not found in any nonpregnant women,” she said, adding that very few pregnant women in their second or third trimester make the high IgG1/low IgG4 that should provide a good response to flu vaccine.

Although Dr. Schlaudecker acknowledged that 80%-90% of the pregnant women in the study had protective HAI titers after immunization, she said the findings have important implications.

“I’m concerned that these low IgG1/high IgG4 ratios seen in pregnant women might actually be giving poor protection against flu infection, which brings us back to the pediatric patients. If pregnant women are not protected well, we are not protecting the babies as well. This suggests that we might need to reconsider approaches to timing of flu vaccine or actually the particular vaccines that we give to pregnant women, and it also shows that pregnancy likely effects systemic responses to things like flu vaccine and other vaccines,” she said.

Dr. Schlaudecker reported having no disclosures.