Reasons Behind ACIP's Off-Label Vaccine Recommendations

VAIL, COLO. – Earlier this year, the Advisory Committee on Immunization Practices took the unusual step of updating recommendations for the use of the meningococcal conjugate vaccines and Tdap vaccine that are at odds with the Food and Drug Administration–approved licensed indications, Dr. Marc Fisher said.

"It’s sort of unusual for ACIP to make off-label indications," Dr. Fischer observed in presenting an update from the Centers for Disease Control and Prevention’s ACIP at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado.

The extraordinary step wasn’t taken lightly. The ACIP issued its off-label recommendations after careful deliberation in an attempt to address several public health problems related to shortcomings in vaccination coverage. These concerns have come to the fore only since licensure of the meningococcal conjugate and Tdap (tetanus toxoid with reduced diphtheria toxoid and acellular pertussis) vaccines.

The committee weighed new data supporting the safety and efficacy of the vaccines in populations that were not included in the licensed indications, explained Dr. Fischer, surveillance and epidemiology chief at the CDC’s Division of Vector-Borne Infectious Diseases in Ft. Collins, Colo. He serves as an ACIP adviser.

For example, the package insert for the MCV4-D meningococcal conjugate vaccine (Menactra) lists a history of Guillain-Barré syndrome as a contraindication to giving the vaccine. However, given the reassuring findings of two population-based studies totaling more than 10 million teens – data which became available only after the product labeling was created – the ACIP has concluded there is no increased risk of Guillain-Barré syndrome after vaccination with MCV4-D. Also, the latest results from the Vaccine Adverse Event Reporting System (VAERS) show no signal of a relationship between the meningococcal conjugate vaccine and Guillain-Barré syndrome.

"So if you’re following the package insert you wouldn’t give the vaccine to an 18-year-old headed off to college who has a history of [Guillain-Barré syndrome], and if you’re following the ACIP recommendation you ignore the history of [Guillain-Barré syndrome] and give the vaccine," Dr. Fischer explained.

Off-label ACIP recommendations for the Tdap vaccine published this year (MMWR 2011;60:13-5) after deliberations at the fall 2010 ACIP meeting include the following:

• Children aged 7-10 years who aren’t fully vaccinated against pertussis should receive a single dose of Tdap.

• Adults aged 65 or older who anticipate having close contact with an infant should get a single dose of Tdap.

• Tdap can now be given regardless of how long it has been since the last dose of a tetanus- or diphtheria-containing vaccine. Tdap is actually licensed for use only 5 years or longer after the last dose.

ACIP took these actions in order to improve pertussis vaccine coverage rates and create a coordinated strategy for preventing disease in young infants. Such a strategy is sorely needed. The incidence of pertussis is highest in children 1 month of age or younger. So is the number of deaths. Moreover, both the absolute number of deaths and the proportion of pertussis-related deaths occurring before age 1 month have increased in each of the past 3 decades. During 2000-2009, fully 78% of all pertussis-related deaths in the United States occurred in infants aged 1 month or younger. "We’re not really solving this problem of deaths in young infants," Dr. Fischer commented.

The new off-label Tdap recommendations address two major gaps in pertussis vaccine coverage stemming from the fact that no pertussis vaccine is licensed for use in children aged 7-10 years or in adults aged 65 and older, even though grandparents and other older adults are now believed to be one of the main sources of infection in young infants.

Filling these two gaps in coverage is a strategy known in immunization circles as cocooning. Cocooning is half of a dual ACIP approach aimed at preventing pertussis in young infants. The other half is embodied in an ACIP recommendation that ob.gyns. should routinely administer Tdap to pregnant women who haven’t previously received the vaccine. This should be done after 20 weeks’ gestation, or – as a second-best alternative –immediately post partum.

"This is a pretty big step, recommending a vaccine during pregnancy," the medical epidemiologist commented.

The committee was swayed in part by a cost-effectiveness analysis which estimated that maternal Tdap vaccination would cost $400,000 per quality-adjusted life-year saved. That’s threefold less than for postpartum maternal vaccination, and 13-fold less costly per quality-adjusted life-year saved than for a cocooning strategy involving vaccination of the child’s parents and grandparents.

ACIP recommended maternal vaccination during pregnancy despite some cautionary evidence that transplacental antibodies may blunt levels of active antibody produced when infants later undergo primary pertussis vaccination. The committee nonetheless decided to act because it’s unclear whether this blunted infant immune response to Tdap is actually clinically significant – and even if it is, the net effect could be to shift cases from the youngest infants to older infants, a group with less-severe disease and a lower case fatality rate. Still, the committee is looking forward to the guidance anticipated to come from an ongoing study of infants born to mothers who received Tdap or tetanus/diphtheria vaccine during their third trimester.

One of the barriers to more effective prevention of invasive meningococcal disease is lack of herd immunity because of insufficient coverage. Only 54% of U.S. 13- to 17-year-olds had received meningococcal vaccine in 2009.

Also, the vaccine’s protective effect appears to be considerably less durable than initially thought. There is mounting evidence of waning immunity by 2-5 years post vaccination. In sum, the evidence suggests that the ACIP’s recommendation at the time of Menactra’s licensure that vaccination routinely occur at the preventive care visit at age 11-12 years "maybe wasn’t the best decision" because it may not protect through the period of highest risk, Dr. Fischer said.

For this reason, this year ACIP has published revised recommendations for the use of meningococcal conjugate vaccines (Menveo and Menactra) in teens, based on a decision made at the fall 2010 ACIP meeting (MMWR 2011;60:72-6). Patients who receive the vaccine at age 11-12 years should get a booster dose at age 16, whereas those who get their first dose at age 13-15 years should have a booster dose at age 16-18. Those who get their first dose at age 16 or later don’t need a booster dose.

The currently available conjugate vaccines cover Neisseria meningitidis serogroups A, C, Y, and W135, but not serogroup B, which predominates among infants. Developing a conjugate vaccine that protects against serogroup B is a high priority. Initial efforts failed because candidate polysaccharide vaccines had molecular mimicry issues predisposing to adverse events. However, several non-polysaccharide vaccines that sidestep such concerns are now in late-stage clinical trials and – if the data prove positive – could be licensed in the next couple of years, according to Dr. Fischer.

Issues of particular interest to primary care physicians that the ACIP is likely to take under consideration within the next year include routine meningococcal conjugate vaccine for infants, hepatitis B vaccine for diabetic adults, and pneumococcal conjugate vaccine for adults, according to Dr. Fischer.

Two additional meningococcal conjugate vaccines are now under Food and Drug Administration review and are likely to be licensed by the end of the year. "I think ACIP is likely to reconsider the issue of routine meningococcal conjugate vaccine for infants in October, with a possible vote on the matter in February," he predicted.

A pneumococcal conjugate vaccine for adults is also likely to be licensed in the coming months, he said. That’s another vaccine the ACIP will consider recommending.

Also on tap for ACIP consideration is the use of human papillomavirus vaccine in males. There’s already a permissive ACIP recommendation for use of the HPV vaccine in males, but since this relatively weak endorsement was issued there have been new data demonstrating the vaccine’s effectiveness in preventing penile cancer, as well as a cost-effectiveness analysis.

Use of the herpes zoster vaccine in 50- to 59-year-olds isn’t recommended by the ACIP at this time. It’s an issue that’s likely to be raised at an upcoming meeting, according to Dr. Fischer.

Routine hepatitis B vaccination in adult diabetic patients as a means of preventing hepatitis outbreaks could come up for a vote as early as ACIP’s October meeting, he said.

Dr. Fischer said he had no relevant financial disclosures.

VAIL, COLO. – Earlier this year, the Advisory Committee on Immunization Practices took the unusual step of updating recommendations for the use of the meningococcal conjugate vaccines and Tdap vaccine that are at odds with the Food and Drug Administration–approved licensed indications, Dr. Marc Fisher said.

"It’s sort of unusual for ACIP to make off-label indications," Dr. Fischer observed in presenting an update from the Centers for Disease Control and Prevention’s ACIP at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado.

The extraordinary step wasn’t taken lightly. The ACIP issued its off-label recommendations after careful deliberation in an attempt to address several public health problems related to shortcomings in vaccination coverage. These concerns have come to the fore only since licensure of the meningococcal conjugate and Tdap (tetanus toxoid with reduced diphtheria toxoid and acellular pertussis) vaccines.

The committee weighed new data supporting the safety and efficacy of the vaccines in populations that were not included in the licensed indications, explained Dr. Fischer, surveillance and epidemiology chief at the CDC’s Division of Vector-Borne Infectious Diseases in Ft. Collins, Colo. He serves as an ACIP adviser.

For example, the package insert for the MCV4-D meningococcal conjugate vaccine (Menactra) lists a history of Guillain-Barré syndrome as a contraindication to giving the vaccine. However, given the reassuring findings of two population-based studies totaling more than 10 million teens – data which became available only after the product labeling was created – the ACIP has concluded there is no increased risk of Guillain-Barré syndrome after vaccination with MCV4-D. Also, the latest results from the Vaccine Adverse Event Reporting System (VAERS) show no signal of a relationship between the meningococcal conjugate vaccine and Guillain-Barré syndrome.

"So if you’re following the package insert you wouldn’t give the vaccine to an 18-year-old headed off to college who has a history of [Guillain-Barré syndrome], and if you’re following the ACIP recommendation you ignore the history of [Guillain-Barré syndrome] and give the vaccine," Dr. Fischer explained.

Off-label ACIP recommendations for the Tdap vaccine published this year (MMWR 2011;60:13-5) after deliberations at the fall 2010 ACIP meeting include the following:

• Children aged 7-10 years who aren’t fully vaccinated against pertussis should receive a single dose of Tdap.

• Adults aged 65 or older who anticipate having close contact with an infant should get a single dose of Tdap.

• Tdap can now be given regardless of how long it has been since the last dose of a tetanus- or diphtheria-containing vaccine. Tdap is actually licensed for use only 5 years or longer after the last dose.

ACIP took these actions in order to improve pertussis vaccine coverage rates and create a coordinated strategy for preventing disease in young infants. Such a strategy is sorely needed. The incidence of pertussis is highest in children 1 month of age or younger. So is the number of deaths. Moreover, both the absolute number of deaths and the proportion of pertussis-related deaths occurring before age 1 month have increased in each of the past 3 decades. During 2000-2009, fully 78% of all pertussis-related deaths in the United States occurred in infants aged 1 month or younger. "We’re not really solving this problem of deaths in young infants," Dr. Fischer commented.

The new off-label Tdap recommendations address two major gaps in pertussis vaccine coverage stemming from the fact that no pertussis vaccine is licensed for use in children aged 7-10 years or in adults aged 65 and older, even though grandparents and other older adults are now believed to be one of the main sources of infection in young infants.

Filling these two gaps in coverage is a strategy known in immunization circles as cocooning. Cocooning is half of a dual ACIP approach aimed at preventing pertussis in young infants. The other half is embodied in an ACIP recommendation that ob.gyns. should routinely administer Tdap to pregnant women who haven’t previously received the vaccine. This should be done after 20 weeks’ gestation, or – as a second-best alternative –immediately post partum.

"This is a pretty big step, recommending a vaccine during pregnancy," the medical epidemiologist commented.

The committee was swayed in part by a cost-effectiveness analysis which estimated that maternal Tdap vaccination would cost $400,000 per quality-adjusted life-year saved. That’s threefold less than for postpartum maternal vaccination, and 13-fold less costly per quality-adjusted life-year saved than for a cocooning strategy involving vaccination of the child’s parents and grandparents.

ACIP recommended maternal vaccination during pregnancy despite some cautionary evidence that transplacental antibodies may blunt levels of active antibody produced when infants later undergo primary pertussis vaccination. The committee nonetheless decided to act because it’s unclear whether this blunted infant immune response to Tdap is actually clinically significant – and even if it is, the net effect could be to shift cases from the youngest infants to older infants, a group with less-severe disease and a lower case fatality rate. Still, the committee is looking forward to the guidance anticipated to come from an ongoing study of infants born to mothers who received Tdap or tetanus/diphtheria vaccine during their third trimester.

One of the barriers to more effective prevention of invasive meningococcal disease is lack of herd immunity because of insufficient coverage. Only 54% of U.S. 13- to 17-year-olds had received meningococcal vaccine in 2009.

Also, the vaccine’s protective effect appears to be considerably less durable than initially thought. There is mounting evidence of waning immunity by 2-5 years post vaccination. In sum, the evidence suggests that the ACIP’s recommendation at the time of Menactra’s licensure that vaccination routinely occur at the preventive care visit at age 11-12 years "maybe wasn’t the best decision" because it may not protect through the period of highest risk, Dr. Fischer said.

For this reason, this year ACIP has published revised recommendations for the use of meningococcal conjugate vaccines (Menveo and Menactra) in teens, based on a decision made at the fall 2010 ACIP meeting (MMWR 2011;60:72-6). Patients who receive the vaccine at age 11-12 years should get a booster dose at age 16, whereas those who get their first dose at age 13-15 years should have a booster dose at age 16-18. Those who get their first dose at age 16 or later don’t need a booster dose.

The currently available conjugate vaccines cover Neisseria meningitidis serogroups A, C, Y, and W135, but not serogroup B, which predominates among infants. Developing a conjugate vaccine that protects against serogroup B is a high priority. Initial efforts failed because candidate polysaccharide vaccines had molecular mimicry issues predisposing to adverse events. However, several non-polysaccharide vaccines that sidestep such concerns are now in late-stage clinical trials and – if the data prove positive – could be licensed in the next couple of years, according to Dr. Fischer.

Issues of particular interest to primary care physicians that the ACIP is likely to take under consideration within the next year include routine meningococcal conjugate vaccine for infants, hepatitis B vaccine for diabetic adults, and pneumococcal conjugate vaccine for adults, according to Dr. Fischer.

Two additional meningococcal conjugate vaccines are now under Food and Drug Administration review and are likely to be licensed by the end of the year. "I think ACIP is likely to reconsider the issue of routine meningococcal conjugate vaccine for infants in October, with a possible vote on the matter in February," he predicted.

A pneumococcal conjugate vaccine for adults is also likely to be licensed in the coming months, he said. That’s another vaccine the ACIP will consider recommending.

Also on tap for ACIP consideration is the use of human papillomavirus vaccine in males. There’s already a permissive ACIP recommendation for use of the HPV vaccine in males, but since this relatively weak endorsement was issued there have been new data demonstrating the vaccine’s effectiveness in preventing penile cancer, as well as a cost-effectiveness analysis.

Use of the herpes zoster vaccine in 50- to 59-year-olds isn’t recommended by the ACIP at this time. It’s an issue that’s likely to be raised at an upcoming meeting, according to Dr. Fischer.

Routine hepatitis B vaccination in adult diabetic patients as a means of preventing hepatitis outbreaks could come up for a vote as early as ACIP’s October meeting, he said.

Dr. Fischer said he had no relevant financial disclosures.

VAIL, COLO. – Earlier this year, the Advisory Committee on Immunization Practices took the unusual step of updating recommendations for the use of the meningococcal conjugate vaccines and Tdap vaccine that are at odds with the Food and Drug Administration–approved licensed indications, Dr. Marc Fisher said.

"It’s sort of unusual for ACIP to make off-label indications," Dr. Fischer observed in presenting an update from the Centers for Disease Control and Prevention’s ACIP at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado.

The extraordinary step wasn’t taken lightly. The ACIP issued its off-label recommendations after careful deliberation in an attempt to address several public health problems related to shortcomings in vaccination coverage. These concerns have come to the fore only since licensure of the meningococcal conjugate and Tdap (tetanus toxoid with reduced diphtheria toxoid and acellular pertussis) vaccines.

The committee weighed new data supporting the safety and efficacy of the vaccines in populations that were not included in the licensed indications, explained Dr. Fischer, surveillance and epidemiology chief at the CDC’s Division of Vector-Borne Infectious Diseases in Ft. Collins, Colo. He serves as an ACIP adviser.

For example, the package insert for the MCV4-D meningococcal conjugate vaccine (Menactra) lists a history of Guillain-Barré syndrome as a contraindication to giving the vaccine. However, given the reassuring findings of two population-based studies totaling more than 10 million teens – data which became available only after the product labeling was created – the ACIP has concluded there is no increased risk of Guillain-Barré syndrome after vaccination with MCV4-D. Also, the latest results from the Vaccine Adverse Event Reporting System (VAERS) show no signal of a relationship between the meningococcal conjugate vaccine and Guillain-Barré syndrome.

"So if you’re following the package insert you wouldn’t give the vaccine to an 18-year-old headed off to college who has a history of [Guillain-Barré syndrome], and if you’re following the ACIP recommendation you ignore the history of [Guillain-Barré syndrome] and give the vaccine," Dr. Fischer explained.

Off-label ACIP recommendations for the Tdap vaccine published this year (MMWR 2011;60:13-5) after deliberations at the fall 2010 ACIP meeting include the following:

• Children aged 7-10 years who aren’t fully vaccinated against pertussis should receive a single dose of Tdap.

• Adults aged 65 or older who anticipate having close contact with an infant should get a single dose of Tdap.

• Tdap can now be given regardless of how long it has been since the last dose of a tetanus- or diphtheria-containing vaccine. Tdap is actually licensed for use only 5 years or longer after the last dose.

ACIP took these actions in order to improve pertussis vaccine coverage rates and create a coordinated strategy for preventing disease in young infants. Such a strategy is sorely needed. The incidence of pertussis is highest in children 1 month of age or younger. So is the number of deaths. Moreover, both the absolute number of deaths and the proportion of pertussis-related deaths occurring before age 1 month have increased in each of the past 3 decades. During 2000-2009, fully 78% of all pertussis-related deaths in the United States occurred in infants aged 1 month or younger. "We’re not really solving this problem of deaths in young infants," Dr. Fischer commented.

The new off-label Tdap recommendations address two major gaps in pertussis vaccine coverage stemming from the fact that no pertussis vaccine is licensed for use in children aged 7-10 years or in adults aged 65 and older, even though grandparents and other older adults are now believed to be one of the main sources of infection in young infants.

Filling these two gaps in coverage is a strategy known in immunization circles as cocooning. Cocooning is half of a dual ACIP approach aimed at preventing pertussis in young infants. The other half is embodied in an ACIP recommendation that ob.gyns. should routinely administer Tdap to pregnant women who haven’t previously received the vaccine. This should be done after 20 weeks’ gestation, or – as a second-best alternative –immediately post partum.

"This is a pretty big step, recommending a vaccine during pregnancy," the medical epidemiologist commented.

The committee was swayed in part by a cost-effectiveness analysis which estimated that maternal Tdap vaccination would cost $400,000 per quality-adjusted life-year saved. That’s threefold less than for postpartum maternal vaccination, and 13-fold less costly per quality-adjusted life-year saved than for a cocooning strategy involving vaccination of the child’s parents and grandparents.

ACIP recommended maternal vaccination during pregnancy despite some cautionary evidence that transplacental antibodies may blunt levels of active antibody produced when infants later undergo primary pertussis vaccination. The committee nonetheless decided to act because it’s unclear whether this blunted infant immune response to Tdap is actually clinically significant – and even if it is, the net effect could be to shift cases from the youngest infants to older infants, a group with less-severe disease and a lower case fatality rate. Still, the committee is looking forward to the guidance anticipated to come from an ongoing study of infants born to mothers who received Tdap or tetanus/diphtheria vaccine during their third trimester.

One of the barriers to more effective prevention of invasive meningococcal disease is lack of herd immunity because of insufficient coverage. Only 54% of U.S. 13- to 17-year-olds had received meningococcal vaccine in 2009.

Also, the vaccine’s protective effect appears to be considerably less durable than initially thought. There is mounting evidence of waning immunity by 2-5 years post vaccination. In sum, the evidence suggests that the ACIP’s recommendation at the time of Menactra’s licensure that vaccination routinely occur at the preventive care visit at age 11-12 years "maybe wasn’t the best decision" because it may not protect through the period of highest risk, Dr. Fischer said.

For this reason, this year ACIP has published revised recommendations for the use of meningococcal conjugate vaccines (Menveo and Menactra) in teens, based on a decision made at the fall 2010 ACIP meeting (MMWR 2011;60:72-6). Patients who receive the vaccine at age 11-12 years should get a booster dose at age 16, whereas those who get their first dose at age 13-15 years should have a booster dose at age 16-18. Those who get their first dose at age 16 or later don’t need a booster dose.

The currently available conjugate vaccines cover Neisseria meningitidis serogroups A, C, Y, and W135, but not serogroup B, which predominates among infants. Developing a conjugate vaccine that protects against serogroup B is a high priority. Initial efforts failed because candidate polysaccharide vaccines had molecular mimicry issues predisposing to adverse events. However, several non-polysaccharide vaccines that sidestep such concerns are now in late-stage clinical trials and – if the data prove positive – could be licensed in the next couple of years, according to Dr. Fischer.

Issues of particular interest to primary care physicians that the ACIP is likely to take under consideration within the next year include routine meningococcal conjugate vaccine for infants, hepatitis B vaccine for diabetic adults, and pneumococcal conjugate vaccine for adults, according to Dr. Fischer.

Two additional meningococcal conjugate vaccines are now under Food and Drug Administration review and are likely to be licensed by the end of the year. "I think ACIP is likely to reconsider the issue of routine meningococcal conjugate vaccine for infants in October, with a possible vote on the matter in February," he predicted.

A pneumococcal conjugate vaccine for adults is also likely to be licensed in the coming months, he said. That’s another vaccine the ACIP will consider recommending.

Also on tap for ACIP consideration is the use of human papillomavirus vaccine in males. There’s already a permissive ACIP recommendation for use of the HPV vaccine in males, but since this relatively weak endorsement was issued there have been new data demonstrating the vaccine’s effectiveness in preventing penile cancer, as well as a cost-effectiveness analysis.

Use of the herpes zoster vaccine in 50- to 59-year-olds isn’t recommended by the ACIP at this time. It’s an issue that’s likely to be raised at an upcoming meeting, according to Dr. Fischer.

Routine hepatitis B vaccination in adult diabetic patients as a means of preventing hepatitis outbreaks could come up for a vote as early as ACIP’s October meeting, he said.

Dr. Fischer said he had no relevant financial disclosures.