NEWS 540
Antigenic sin:
Consent concerns:
Microbial models:
Newer vaccines expose immunogenic questions
New provisions for newborn screenings raise objections
Scientists explore ways to study the microbiome
542
543
npg
© 2015 Nature America, Inc. All rights reserved.
Updated, augmented vaccines compete with original antigenic sin In late December 2014, Sony Salzman, a 25-year-old living in New York City, heard about the approval of Gardasil 9, the latest human papillomavirus (HPV) vaccine created by Merck, and called her gynecologist to ask about the vaccine. Having been vaccinated eight years ago with the previous version, simply called Gardasil, Salzman was interested in receiving the improved version of the vaccine. “But the folks at the doctor’s office had no idea there was even a new version,” Salzman says. Chalking their ignorance up to the relative newness of the vaccine—it had only been approved by the US Food and Drug Administration (FDA) on 10 December— Salzman waited and then asked again in April 2015. “I didn’t get a very clear answer on whether I could get the vaccine,” Salzman says. “But I would definitely like to get revaccinated, if I’m eligible.” According to 2013 estimates by the US Centers for Disease Control and Prevention (CDC), about 58% of girls and young women and 35% of boys and young men in the US between the ages of 13 and 17 received at least one dose of Gardasil. Many of those individuals, like Salzman, will now be considering whether to get revaccinated with Gardasil 9. What differentiates Gardasil 9 from the previous version is that Gardasil 9 includes nine strains of HPV—6, 11, 16, 18, 31, 33, 45, 52 and 58—whereas Gardasil only includes the first four of these strains. The motivation behind expanding the number of strains included in the vaccine is to offer broader protection. “The five additional strains cause an additional 20% of cervical cancers,” explains Michelle Vichnin, Merck’s medical director for adolescent vaccines. What worries some researchers is that individuals who already received vaccination against HPV will not respond to the augmented vaccine version with more strains because of an immunological concept known as ‘original antigenic sin.’ “Original sin is a Biblical term and it goes back to the sin of Adam that is on all of us,” says Joshy Jacob, an immunologist at 540
more of these updated vaccines are hitting the market. In 2010, for example, Pfizer doled out Prevnar 13 (PCV13), an updated version of its pneumococcal vaccine Prevnar 7 (PCV7). PCV13 included six more pneumococcal disease–causing serotypes than PCV7. However, according to at least one study, no effects of original antigenic sin were observed in older children or adolescents who were given one dose of PCV13 after previously having received PCV7 (Pediatr. Infect. Dis. J., 33, 183–189). Meanwhile, in October 2014, the FDA approved the first meningococcal vaccine that targets the B strain of the meningococcal bacteria; other available vaccines target four of the total five strains that lead to disease—A, C, Y and W. This new vaccine, called Trumenba and manufactured by Pfizer, along with a second meningococcal B Not the first time vaccine, called Bexsero and made by Novartis, The issue of original antigenic sin is not have been recommended by the Advisory unique to HPV. In the case of dengue, for Committee on Immunization Practices example, which has four known serotypes, (ACIP), a branch of the CDC, for use in those the similarity between these different types who are at increased risk for meningococcal has been known to cause memory B and T disease, such as those who have been exposed cells to be re-activated to meningococcal B during secondary during an outbreak. Ian “If you could prevent infection. As a result, the Branam, a spokesperson an additional 4,000 reactivated responses— for the CDC told Nature due to skewing towards Medicine that, “The deaths from cancer the primary infecting ACIP Meningococcal per year down the virus—may have Vaccines Work Group been less optimal for has been collecting and road, isn’t that of targeting the secondary reviewing all available value?” infecting virus. (Nat. Rev. data about serogroup B Immunol., 11, 532–543, meningococcal vaccines 2011). This was challenged, however, in a related to healthy adolescents.” As such, 2013 study: researchers found the response to it has not yet expanded the vaccination a secondary virus was actually more targeted recommendation to include individuals who towards regions conserved with the primary are not at high risk. But, “In general,” Branam infecting virus, suggesting in this instance that adds, “The Work Group is not concerned original antigenic sin could play a protective with the issue” of original antigenic sin when role. (Proc. Natl. Acad. Sci., 110, E2046–E2053, it comes to the meningococcal B vaccine. 2013). The matter of original antigenic sin is an Gardasil challenge important one, as drug developers make When it comes to the label recommendation improved versions of already available for revaccination with Gardasil 9, some vaccines by adapting them to protect against questions loom. In February, the ACIP more strains of the same pathogen. More and voted to recommend Gardasil 9 as one of Emory Vaccines Center in Atlanta. The idea is that when the immune system encounters antigens that are related to antigens that it has previously encountered, memory cell responses and antibodies against the first antigen are recalled first instead of a primary response against the new antigen. “Whatever you’re exposed to first antigenically, you bear that ‘sin’ for the rest of your life,” Jacob says. When it comes to original antigenic sin, the naïve responses may be at a disadvantage when summoned at the same time as the primed responses. “If the rookies are on the same team as the all-stars, then the rookie is not going to get called up as much,” explains Andrea Sant, an immunologist at the University of Rochester Medical Center in upstate New York. “The playing field is not level.”
VOLUME 21 | NUMBER 6 | JUNE 2015 NATURE MEDICINE
npg
© 2015 Nature America, Inc. All rights reserved.
Merck
NEWS
Second shot: Gardasil 9's approval poses questions of revaccination.
three possible vaccines a person could get to help prevent HPV infection or one of the cancers caused by the virus. However, the ACIP meeting in February was cut short owing to weather concerns, so the discussion surrounding revaccination was postponed. Consequently, the topic of revaccination with Gardasil 9 may come up at the end of June when the ACIP will have the second of its three annual meetings in Atlanta. The current indication for Gardasil 9, which was approved by the FDA in December 2014, is for boys and girls who have never been vaccinated with any type of HPV vaccine before. Merck has tested Gardasil 9 in girls and women who have already received the older, quadrivalent version of Gardasil, but so far these tests have only looked at safety and immunogenicity. Preliminary unpublished results from this trial showed that the production of antibodies against the four viral types common to both versions of the vaccine increased slightly in this group compared with those who received Gardasil 9 and had never been previously immunized against HPV. However, antibody titers against the five added viral strains in Gardasil 9 among the former group were only 25% and 63% of that seen in people who received Gardasil 9 alone. Merck is reluctant to provide advice on revaccination on the basis of these preliminary results. “We don’t know what [the reduced antibody titer] means,” Vichnin says. “This information is provided to physicians and patients, and it’s an individual decision.”
The ACIP has also hesitated to make a recommendation. “There’s some data but it’s mostly safety data,” Markowitz says. “But there’s not an indication for revaccination on the label [of the vaccine].” There have been cost-effectiveness data collected by the CDC but they haven’t been formally presented yet. How much is enough The reduced antibody titers in previously vaccinated people are not surprising to immunologists. “I think it’s fascinating what they found,” Sant says. “But it doesn’t surprise me at all.” But how it will play out in the rollout of the new vaccine is unknown. “My question is, ‘is the antibody titer reduced to the point that it’s no longer protective?’” asks Paul Offit, director of the Vaccines Education Center at the Children’s Hospital of Philadelphia. “I think it’s likely to be enough.” Offit further explains that when Gardasil was first approved in June 2006, it was only recommended for use in girls and young women. “At the time, we had evidence that the vaccine prevented infection in boys, but no evidence yet that it would prevent cancer in boys,” he says. As a result, Gardasil continues to be widely perceived as a vaccine for girls, Offit explains. It wasn’t until 2011, when data that the vaccine also helped prevent cancer in boys became available, that Gardasil was also recommended for use in boys and young men. Offit worries that a similar delay in recommending Gardasil 9 for use over the older version of Gardasil, as well as over GlaxoSmithKline’s Cervarix, a version of HPV vaccine against two strains of virus,
NATURE MEDICINE VOLUME 21 | NUMBER 6 | JUNE 2015
could cause long-term effects. According to the CDC, more than 12,000 cases of cervical cancer were diagnosed in 2011 in the US, the most recent year for which statistics are available. Roughly 4,000 of these cases ended in deaths. “If you could prevent an additional 4,000 deaths from cancer per year down the road, isn’t that of value?” Offit asks. “Yes, it’s of value.” Sant suggests that the reduced antibody titer may be overcome by giving a vaccine with only the five new HPV strains in Garadsil 9 to those who have received the earlier quadravalent version. “I’d think it makes sense to offer them separately,” Sant says. That way, the body is able to mount a full response against the five new viral strains. Another option is to try a different adjuvant, says Jacob. An adjuvant is an ingredient added to a vaccine that helps create a stronger immune response, so changing the adjuvant in Gardasil 9 from the current aluminum-based compound to an oil-in-water–based adjuvant might prove effective, Jacob suggests. In a 2012 paper, for example, Jacob and colleagues showed that in mice that were revaccinated with a flu vaccine containing strains of flu virus that they had previously been exposed to as well as a new viral strain, the addition of an adjuvant called squalene oil-in-water allowed the mice to respond better to the new virus (Proc. Natl. Acad. Sci., 109, 13751–13756, 2012). But from Merck’s point of view, the time and money it would take to create a vaccine exclusively for revaccination is not something in which the company is looking to invest. “We put the redundancy [of the four Gardasil strains] in so that we could offer broader protection moving forward,” Vichnin says. Merck’s plan is also to eventually have Gardasil 9 replace Gardasil, but there is no concrete plan for this transition yet. Neither Merck nor the ACIP has any plans to conduct a study to evaluate the efficacy of Gardasil 9 in individuals who have received the previous, quadrivalent form of the vaccine. GlaxoSmithKline, meanwhile, has no current plans to create an expanded version of its HPV vaccine, a company spokesperson told Nature Medicine. “I think really the focus, frankly, from the medical community is, ‘Let’s get vaccine into boys and girls who haven’t been vaccinated yet,’” Vichnin says. “While revaccination is interesting and it’s a common question, from a Merck standpoint, we provide the information and it’s going to be up to the providers and the public health community.” Shraddha Chakradhar 541
Antigenic sin:
Consent concerns:
Microbial models:
Newer vaccines expose immunogenic questions
New provisions for newborn screenings raise objections
Scientists explore ways to study the microbiome
542
543
npg
© 2015 Nature America, Inc. All rights reserved.
Updated, augmented vaccines compete with original antigenic sin In late December 2014, Sony Salzman, a 25-year-old living in New York City, heard about the approval of Gardasil 9, the latest human papillomavirus (HPV) vaccine created by Merck, and called her gynecologist to ask about the vaccine. Having been vaccinated eight years ago with the previous version, simply called Gardasil, Salzman was interested in receiving the improved version of the vaccine. “But the folks at the doctor’s office had no idea there was even a new version,” Salzman says. Chalking their ignorance up to the relative newness of the vaccine—it had only been approved by the US Food and Drug Administration (FDA) on 10 December— Salzman waited and then asked again in April 2015. “I didn’t get a very clear answer on whether I could get the vaccine,” Salzman says. “But I would definitely like to get revaccinated, if I’m eligible.” According to 2013 estimates by the US Centers for Disease Control and Prevention (CDC), about 58% of girls and young women and 35% of boys and young men in the US between the ages of 13 and 17 received at least one dose of Gardasil. Many of those individuals, like Salzman, will now be considering whether to get revaccinated with Gardasil 9. What differentiates Gardasil 9 from the previous version is that Gardasil 9 includes nine strains of HPV—6, 11, 16, 18, 31, 33, 45, 52 and 58—whereas Gardasil only includes the first four of these strains. The motivation behind expanding the number of strains included in the vaccine is to offer broader protection. “The five additional strains cause an additional 20% of cervical cancers,” explains Michelle Vichnin, Merck’s medical director for adolescent vaccines. What worries some researchers is that individuals who already received vaccination against HPV will not respond to the augmented vaccine version with more strains because of an immunological concept known as ‘original antigenic sin.’ “Original sin is a Biblical term and it goes back to the sin of Adam that is on all of us,” says Joshy Jacob, an immunologist at 540
more of these updated vaccines are hitting the market. In 2010, for example, Pfizer doled out Prevnar 13 (PCV13), an updated version of its pneumococcal vaccine Prevnar 7 (PCV7). PCV13 included six more pneumococcal disease–causing serotypes than PCV7. However, according to at least one study, no effects of original antigenic sin were observed in older children or adolescents who were given one dose of PCV13 after previously having received PCV7 (Pediatr. Infect. Dis. J., 33, 183–189). Meanwhile, in October 2014, the FDA approved the first meningococcal vaccine that targets the B strain of the meningococcal bacteria; other available vaccines target four of the total five strains that lead to disease—A, C, Y and W. This new vaccine, called Trumenba and manufactured by Pfizer, along with a second meningococcal B Not the first time vaccine, called Bexsero and made by Novartis, The issue of original antigenic sin is not have been recommended by the Advisory unique to HPV. In the case of dengue, for Committee on Immunization Practices example, which has four known serotypes, (ACIP), a branch of the CDC, for use in those the similarity between these different types who are at increased risk for meningococcal has been known to cause memory B and T disease, such as those who have been exposed cells to be re-activated to meningococcal B during secondary during an outbreak. Ian “If you could prevent infection. As a result, the Branam, a spokesperson an additional 4,000 reactivated responses— for the CDC told Nature due to skewing towards Medicine that, “The deaths from cancer the primary infecting ACIP Meningococcal per year down the virus—may have Vaccines Work Group been less optimal for has been collecting and road, isn’t that of targeting the secondary reviewing all available value?” infecting virus. (Nat. Rev. data about serogroup B Immunol., 11, 532–543, meningococcal vaccines 2011). This was challenged, however, in a related to healthy adolescents.” As such, 2013 study: researchers found the response to it has not yet expanded the vaccination a secondary virus was actually more targeted recommendation to include individuals who towards regions conserved with the primary are not at high risk. But, “In general,” Branam infecting virus, suggesting in this instance that adds, “The Work Group is not concerned original antigenic sin could play a protective with the issue” of original antigenic sin when role. (Proc. Natl. Acad. Sci., 110, E2046–E2053, it comes to the meningococcal B vaccine. 2013). The matter of original antigenic sin is an Gardasil challenge important one, as drug developers make When it comes to the label recommendation improved versions of already available for revaccination with Gardasil 9, some vaccines by adapting them to protect against questions loom. In February, the ACIP more strains of the same pathogen. More and voted to recommend Gardasil 9 as one of Emory Vaccines Center in Atlanta. The idea is that when the immune system encounters antigens that are related to antigens that it has previously encountered, memory cell responses and antibodies against the first antigen are recalled first instead of a primary response against the new antigen. “Whatever you’re exposed to first antigenically, you bear that ‘sin’ for the rest of your life,” Jacob says. When it comes to original antigenic sin, the naïve responses may be at a disadvantage when summoned at the same time as the primed responses. “If the rookies are on the same team as the all-stars, then the rookie is not going to get called up as much,” explains Andrea Sant, an immunologist at the University of Rochester Medical Center in upstate New York. “The playing field is not level.”
VOLUME 21 | NUMBER 6 | JUNE 2015 NATURE MEDICINE
npg
© 2015 Nature America, Inc. All rights reserved.
Merck
NEWS
Second shot: Gardasil 9's approval poses questions of revaccination.
three possible vaccines a person could get to help prevent HPV infection or one of the cancers caused by the virus. However, the ACIP meeting in February was cut short owing to weather concerns, so the discussion surrounding revaccination was postponed. Consequently, the topic of revaccination with Gardasil 9 may come up at the end of June when the ACIP will have the second of its three annual meetings in Atlanta. The current indication for Gardasil 9, which was approved by the FDA in December 2014, is for boys and girls who have never been vaccinated with any type of HPV vaccine before. Merck has tested Gardasil 9 in girls and women who have already received the older, quadrivalent version of Gardasil, but so far these tests have only looked at safety and immunogenicity. Preliminary unpublished results from this trial showed that the production of antibodies against the four viral types common to both versions of the vaccine increased slightly in this group compared with those who received Gardasil 9 and had never been previously immunized against HPV. However, antibody titers against the five added viral strains in Gardasil 9 among the former group were only 25% and 63% of that seen in people who received Gardasil 9 alone. Merck is reluctant to provide advice on revaccination on the basis of these preliminary results. “We don’t know what [the reduced antibody titer] means,” Vichnin says. “This information is provided to physicians and patients, and it’s an individual decision.”
The ACIP has also hesitated to make a recommendation. “There’s some data but it’s mostly safety data,” Markowitz says. “But there’s not an indication for revaccination on the label [of the vaccine].” There have been cost-effectiveness data collected by the CDC but they haven’t been formally presented yet. How much is enough The reduced antibody titers in previously vaccinated people are not surprising to immunologists. “I think it’s fascinating what they found,” Sant says. “But it doesn’t surprise me at all.” But how it will play out in the rollout of the new vaccine is unknown. “My question is, ‘is the antibody titer reduced to the point that it’s no longer protective?’” asks Paul Offit, director of the Vaccines Education Center at the Children’s Hospital of Philadelphia. “I think it’s likely to be enough.” Offit further explains that when Gardasil was first approved in June 2006, it was only recommended for use in girls and young women. “At the time, we had evidence that the vaccine prevented infection in boys, but no evidence yet that it would prevent cancer in boys,” he says. As a result, Gardasil continues to be widely perceived as a vaccine for girls, Offit explains. It wasn’t until 2011, when data that the vaccine also helped prevent cancer in boys became available, that Gardasil was also recommended for use in boys and young men. Offit worries that a similar delay in recommending Gardasil 9 for use over the older version of Gardasil, as well as over GlaxoSmithKline’s Cervarix, a version of HPV vaccine against two strains of virus,
NATURE MEDICINE VOLUME 21 | NUMBER 6 | JUNE 2015
could cause long-term effects. According to the CDC, more than 12,000 cases of cervical cancer were diagnosed in 2011 in the US, the most recent year for which statistics are available. Roughly 4,000 of these cases ended in deaths. “If you could prevent an additional 4,000 deaths from cancer per year down the road, isn’t that of value?” Offit asks. “Yes, it’s of value.” Sant suggests that the reduced antibody titer may be overcome by giving a vaccine with only the five new HPV strains in Garadsil 9 to those who have received the earlier quadravalent version. “I’d think it makes sense to offer them separately,” Sant says. That way, the body is able to mount a full response against the five new viral strains. Another option is to try a different adjuvant, says Jacob. An adjuvant is an ingredient added to a vaccine that helps create a stronger immune response, so changing the adjuvant in Gardasil 9 from the current aluminum-based compound to an oil-in-water–based adjuvant might prove effective, Jacob suggests. In a 2012 paper, for example, Jacob and colleagues showed that in mice that were revaccinated with a flu vaccine containing strains of flu virus that they had previously been exposed to as well as a new viral strain, the addition of an adjuvant called squalene oil-in-water allowed the mice to respond better to the new virus (Proc. Natl. Acad. Sci., 109, 13751–13756, 2012). But from Merck’s point of view, the time and money it would take to create a vaccine exclusively for revaccination is not something in which the company is looking to invest. “We put the redundancy [of the four Gardasil strains] in so that we could offer broader protection moving forward,” Vichnin says. Merck’s plan is also to eventually have Gardasil 9 replace Gardasil, but there is no concrete plan for this transition yet. Neither Merck nor the ACIP has any plans to conduct a study to evaluate the efficacy of Gardasil 9 in individuals who have received the previous, quadrivalent form of the vaccine. GlaxoSmithKline, meanwhile, has no current plans to create an expanded version of its HPV vaccine, a company spokesperson told Nature Medicine. “I think really the focus, frankly, from the medical community is, ‘Let’s get vaccine into boys and girls who haven’t been vaccinated yet,’” Vichnin says. “While revaccination is interesting and it’s a common question, from a Merck standpoint, we provide the information and it’s going to be up to the providers and the public health community.” Shraddha Chakradhar 541
