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      Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older — United States, 2019

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      , MD 1 , , , MD 2
      Morbidity and Mortality Weekly Report
      Centers for Disease Control and Prevention

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          Abstract

          In October 2018, the Advisory Committee on Immunization Practices (ACIP)* voted to recommend approval of the Recommended Immunization Schedule for Adults, Aged 19 Years or Older, United States, 2019. The 2019 adult immunization schedule, available at https://www.cdc.gov/vaccines/schedules, † summarizes ACIP recommendations in two tables and accompanying notes. The 2019 adult immunization schedule has been approved by the CDC Director, the American College of Physicians, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Nurse-Midwives. ACIP’s recommendations on use of each vaccine are developed after in-depth reviews of vaccine-related data, including disease epidemiology and burden, vaccine efficacy and effectiveness, vaccine safety, quality of evidence, feasibility of program implementation, and economic analyses of immunization policy ( 1 ). The adult immunization schedule is published annually to consolidate and summarize updates to ACIP recommendations on vaccination of adults and assist health care providers in implementing current ACIP recommendations. The use of trade names of vaccines in this report and in the adult immunization schedule is for identification purposes only and does not imply endorsement by ACIP or CDC. For further guidance on the use of vaccines in the adult immunization schedule, health care providers should refer to the full ACIP recommendations at https://www.cdc.gov/vaccines/hcp/acip-recs/index.html. Changes in recommended use of vaccines can occur between annual updates to the adult immunization schedule. These changes, if made, are available at https://www.cdc.gov/vaccines/acip/recommendations.html. § Printable versions of the 2019 adult immunization schedule and instructions for ordering printed copies are available at https://www.cdc.gov/vaccines/schedules/hcp/adult.html#note. The 2019 adult immunization schedule is a product of extensive formal usability testing of 2017 and 2018 adult immunization schedules, including in-depth interviews with 48 primary care physicians, nurse practitioners, physician assistants, pharmacists, nurses, and medical assistants, who reported being familiar with the adult immunization schedule, and an Internet survey of 251 internal medicine and family medicine physicians to assess their impressions and preferences on redesigned drafts of the adult immunization schedule ( 2 ). In addition to incorporating new ACIP recommendations on influenza, hepatitis A, and hepatitis B vaccinations, each vaccination section in the 2019 adult immunization schedule was revised for clarity, brevity, and, for vaccines that also appear in the 2019 child and adolescent immunization schedule ( 3 ), consistency between the two schedules. Because usability testing found that providers rarely used the table of contraindications and precautions for vaccines recommended for adults that was a part of previous iterations of the adult immunization schedule, the table was removed from the 2019 adult immunization schedule. Information on vaccine contraindications and precautions is available at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs. Changes in the 2019 Adult Immunization Schedule: Updated ACIP Recommendations Influenza Vaccination. In June 2018, ACIP updated recommendations on the use of live attenuated influenza vaccine (LAIV) (FluMist Quadrivalent, AstraZeneca) after two influenza seasons (2016–17 and 2017–18), during which use of LAIV was not recommended in the United States ( 4 ). For the 2018–19 season, any licensed influenza vaccine that is recommended for age and health status of the patient may be used. LAIV is an option for adults aged ≤49 years, except those who 1) have immunocompromising conditions, including human immunodeficiency virus (HIV) infection; 2) have anatomic or functional asplenia; 3) are pregnant; 4) have close contact with or are caregivers of severely immunocompromised persons in a protected environment; 5) have received influenza antiviral medications in the previous 48 hours; or 6) have a cerebrospinal fluid leak or a cochlear implant. Adults with a history of Guillain-Barré syndrome within 6 weeks of receipt of a previous dose of influenza vaccine generally should not receive influenza vaccine. Hepatitis B Vaccination. In February 2018, ACIP recommended use of the new single-antigen recombinant hepatitis B vaccine with a novel cytosine-phosphate-guanine 1018 oligodeoxynucleotide adjuvant (Heplisav-B, Dynavax) for prevention of hepatitis B virus infection in adults aged ≥18 years ( 5 ). Approved by the Food and Drug Administration in November 2017, Heplisav-B is routinely administered in 2 doses given ≥4 weeks apart. It can be used as a substitute in a 3-dose series with a different hepatitis B vaccine, but a valid 2-dose series requires 2 doses of Heplisav-B with ≥4 weeks between doses. When feasible, a vaccine from the same manufacturer should be used to complete the vaccination series. However, vaccination should not be deferred if the previously administered hepatitis B vaccine is unknown or if a vaccine from the same manufacturer is not available. A pregnant woman with an indication for hepatitis B vaccination should not receive Heplisav-B because no safety data are available on its use during pregnancy. Hepatitis A Vaccination. In October 2018, ACIP recommended adding homelessness as an indication for routine hepatitis A vaccination with a 2-dose series of single-antigen hepatitis A vaccine (Havrix, GlaxoSmithKline; Vaqta, Merck) or a 3-dose series of combination hepatitis A and hepatitis B vaccine (Twinrix, GlaxoSmithKline) ( 6 ). Other populations at increased risk for hepatitis A virus infection or severe hepatitis A disease and recommended to receive vaccination include 1) persons with chronic liver disease or clotting factor disorders; 2) travelers in countries with high or intermediate hepatitis A endemicity; 3) persons with close personal contact with an international adoptee in the first 60 days after arrival from a country with high or endemic hepatitis A prevalence; 4) men who have sex with men; 5) persons who use injection or noninjection drugs; and 6) persons who work with hepatitis A virus in a laboratory or with nonhuman primates infected with the virus ( 7 – 9 ). In addition, any person who is not at risk for hepatitis A virus infection but wants protection against it may be vaccinated. Changes in the 2019 Adult Immunization Schedule: Revised Content, Format, and Graphics Cover. Recommended Adult Immunization Schedule. The cover page of the 2019 adult immunization schedule has been simplified and contains the following changes: Features a shortened title, provides basic instructions on how to use the adult immunization schedule to systematically identify vaccination needs of adults, and lists routinely recommended vaccines and their standardized abbreviations and trade names. Includes web links through which health care providers can download the CDC Vaccine Schedules App and access reference materials on surveillance of vaccine-preventable diseases, including case identification and disease outbreak response. Simplifies instructions for reporting suspected cases of reportable vaccine-preventable diseases to local or state health departments and for reporting postvaccination adverse events and serious adverse events to the Vaccine Adverse Event Reporting System; information on the Vaccine Injury Compensation Program; and links to other resources, such as Vaccine Information Statements and recommended vaccines for travelers. Table 1. Recommended Adult Immunization Schedule by Age Group. Table 1 (previously known as Figure 1) describes routine and catch-up vaccination recommendations for adults by age. ACIP recommends routine annual influenza vaccination for all persons aged ≥6 months who do not have contraindications; 1 annual dose of IIV, RIV, or LAIV that is appropriate for age and health status of the vaccine recipient is recommended. Table 1 contains the following change: Lists LAIV separately from inactivated influenza vaccine (IIV) (many branded products) and recombinant influenza vaccine (RIV) (Flublok Quadrivalent, Sanofi Pasteur) for adults aged ≤49 years. Table 2. Recommended Adult Immunization Schedule by Medical Condition and Other Indications. Table 2 (previously known as Figure 2) describes indications for which vaccines, if not previously administered, should be administered unless noted otherwise. Table 2 contains the following changes: Lists LAIV separately from IIV and RIV. Contains two new display colors for some vaccines: orange and pink. Orange indicates “Precaution—vaccine might be indicated if benefit of protection outweighs risk of adverse reaction”; pink indicates “Delay vaccination until after pregnancy if vaccine is indicated.” Designates the use of LAIV in pregnant women and immunocompromised adults, including those with HIV infection, as “Contraindicated—vaccine should not be administered because of risk for serious adverse reaction” (red). The risk for associated adverse effects from the use of LAIV in adults with functional or anatomic asplenia or complement deficiencies is not known; however, the use of LAIV in this population has also been designated as “Contraindicated” (red). For adults with end-stage renal disease, heart or lung disease, chronic liver disease, or diabetes, the use of LAIV has been given the “Precaution” (orange) designation. Designates the use of serogroup B meningococcal vaccine (MenB) (Bexsero, GlaxoSmithKline; Trumenba, Pfizer) in pregnant women as “Precaution” (orange). MenB should be deferred in pregnant women unless they are at increased risk for serogroup B meningococcal disease and the benefits of vaccination are considered to outweigh potential risks ( 10 ). Maintains the use of meningococcal serogroups A, C, W-135, and Y conjugate vaccine (MenACWY) (Menactra, Sanofi Pasteur; Menveo, GlaxoSmithKline) in pregnant women as “Recommended vaccination for adults with an additional risk factor or another indication” (purple). In contrast to the recommendation to defer administration of MenB vaccine to pregnant women, pregnancy should not preclude the use of MenACWY vaccine if it is otherwise indicated ( 11 ). Designates the use of human papillomavirus (HPV) vaccine (Gardasil 9, Merck) and recombinant zoster vaccine (RZV) (Shingrix, GlaxoSmithKline) in pregnant women as “Delay until after pregnancy” (pink). The use of HPV vaccine is not recommended for pregnant women ( 12 , 13 ). Pregnant women should consider delaying receipt of RZV, if it is indicated, until after pregnancy ( 14 ). Live attenuated zoster vaccine (Zostavax, Merck) is contraindicated during pregnancy ( 15 ). Notes. Recommended Adult Immunization Schedule. Each routinely recommended vaccine for adults in Tables 1 and 2 is accompanied by notes (previously known as footnotes), designed to provide additional information about routine vaccination and recommendations in special situations. The notes contain the following format changes: Lists vaccination sections alphabetically (superscript footnote numbers in the former figures [now tables] have been removed). Contains concise information describing vaccine indications, dosing frequencies and intervals, and other published ACIP recommendations for each section. Includes new recommendations on influenza, hepatitis B, and hepatitis A vaccines in their respective sections. Removes recommendations for vaccination in outbreak settings in measles, mumps, and rubella, and meningococcal vaccination notes. Additional Information The Recommended Adult Immunization Schedule, United States, 2019, is available at https://www.cdc.gov/vaccines/schedules/hcp/adult.html and in the Annals of Internal Medicine ( 16 ). The full ACIP recommendations for each vaccine are also available at https://www.cdc.gov/vaccines/hcp/acip-recs/index.html. All vaccines identified in Tables 1 and 2 (except zoster vaccines) also appear in the Recommended Immunization Schedule for Children and Adolescents, United States, 2019 ( 3 ). The notes for vaccines that appear in both the adult immunization schedule and the child and adolescent immunization schedule have been harmonized to the greatest extent possible.

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          Use of 9-Valent Human Papillomavirus (HPV) Vaccine: Updated HPV Vaccination Recommendations of the Advisory Committee on Immunization Practices

          During its February 2015 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended 9-valent human papillomavirus (HPV) vaccine (9vHPV) (Gardasil 9, Merck and Co., Inc.) as one of three HPV vaccines that can be used for routine vaccination (Table 1). HPV vaccine is recommended for routine vaccination at age 11 or 12 years (1). ACIP also recommends vaccination for females aged 13 through 26 years and males aged 13 through 21 years not vaccinated previously. Vaccination is also recommended through age 26 years for men who have sex with men and for immunocompromised persons (including those with HIV infection) if not vaccinated previously (1). 9vHPV is a noninfectious, virus-like particle (VLP) vaccine. Similar to quadrivalent HPV vaccine (4vHPV), 9vHPV contains HPV 6, 11, 16, and 18 VLPs. In addition, 9vHPV contains HPV 31, 33, 45, 52, and 58 VLPs (2). 9vHPV was approved by the Food and Drug Administration (FDA) on December 10, 2014, for use in females aged 9 through 26 years and males aged 9 through 15 years (3). For these recommendations, ACIP reviewed additional data on 9vHPV in males aged 16 through 26 years (4). 9vHPV and 4vHPV are licensed for use in females and males. Bivalent HPV vaccine (2vHPV), which contains HPV 16, 18 VLPs, is licensed for use in females (1). This report summarizes evidence considered by ACIP in recommending 9vHPV as one of three HPV vaccines that can be used for vaccination and provides recommendations for vaccine use. Recommendations for routine use of vaccines in children, adolescents and adults are developed by the Advisory Committee on Immunization Practices (ACIP). ACIP is chartered as a federal advisory committee to provide expert external advice and guidance to the Director of the Centers for Disease Control and Prevention (CDC) on use of vaccines and related agents for the control of vaccine-preventable diseases in the civilian population of the United States. Recommendations for routine use of vaccines in children and adolescents are harmonized to the greatest extent possible with recommendations made by the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Obstetricians and Gynecologists (ACOG). Recommendations for routine use of vaccines in adults are harmonized with recommendations of AAFP, ACOG, and the American College of Physicians (ACP). ACIP recommendations approved by the CDC Director become agency guidelines on the date published in the Morbidity and Mortality Weekly Report (MMWR). Additional information about ACIP is available at http://www.cdc.gov/vaccines/acip/. Methods From October 2013 to February 2015, the ACIP HPV Vaccine Work Group reviewed clinical trial data assessing the efficacy, immunogenicity, and safety of 9vHPV, modeling data on cost-effectiveness of 9vHPV, and data on burden of type-specific HPV-associated disease in the United States. Summaries of reviewed evidence and Work Group discussions were presented to ACIP before recommendations were proposed. Recommendations were approved by ACIP in February 2015. Evidence supporting 9vHPV use was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (5) and determined to be type 2 (moderate level of evidence) among females and 3 (low level of evidence) among males; the recommendation was categorized as a Category A recommendation (for all persons in an age- or risk-factor–based group) (6). HPV-Associated Disease HPV is associated with cervical, vulvar, and vaginal cancer in females, penile cancer in males, and anal cancer and oropharyngeal cancer in both females and males (7–10). The burden of HPV infection also includes cervical precancers, including cervical intraepithelial neoplasia grade 2 or 3 and adenocarcinoma in situ (≥CIN2). The majority of all HPV-associated cancers are caused by HPV 16 or 18, types targeted by 2vHPV, 4vHPV and 9vHPV (2,11,12). In the United States, approximately 64% of invasive HPV-associated cancers are attributable to HPV 16 or 18 (65% for females; 63% for males; approximately 21,300 cases annually) and 10% are attributable to the five additional types in 9vHPV: HPV 31, 33, 45, 52, and 58 (14% for females; 4% for males; approximately 3,400 cases annually) (1,12,13). HPV 16 or 18 account for 66% and the five additional types for about 15% of cervical cancers (12). Approximately 50% of ≥CIN2 are caused by HPV 16 or 18 and 25% by HPV 31, 33, 45, 52, or 58 (14). HPV 6 or 11 cause 90% of anogenital warts (condylomata) and most cases of recurrent respiratory papillomatosis (15). 9vHPV Efficacy, Immunogenicity, and Safety In a phase III efficacy trial comparing 9vHPV with 4vHPV among approximately 14,000 females aged 16 through 26 years, 9vHPV efficacy for prevention of ≥CIN2, vulvar intraepithelial neoplasia grade 2 or 3, and vaginal intraepithelial neoplasia grade 2 or 3 caused by HPV 31, 33, 45, 52, or 58 was 96.7% in the per protocol population* (Table 2) (2,16). Efficacy for prevention of ≥CIN2 caused by HPV 31, 33, 45, 52, or 58 was 96.3% and for 6-month persistent infection was 96.0% (16). Few cases were caused by HPV 6, 11, 16, or 18 in either vaccine group. Noninferior immunogenicity of 9vHPV compared with 4vHPV was used to infer efficacy for HPV 6, 11, 16, and 18. Geometric mean antibody titers (GMTs) 1 month after the third dose were noninferior for HPV 6, 11, 16, and 18; in the 9vHPV group, >99% seroconverted to all nine HPV vaccine types (Table 3). Two immunobridging trials were conducted. One compared 9vHPV in approximately 2,400 females and males aged 9 through 15 years with approximately 400 females aged 16 through 26 years. Over 99% seroconverted to all nine HPV vaccine types; GMTs were significantly higher in adolescents aged 9 through 15 years compared with females aged 16 through 26 years. In a comparison of 4vHPV with 9vHPV in approximately 600 adolescent females aged 9 through 15 years, 100% seroconverted to HPV 6, 11, 16, and 18 in both groups, and GMTs were noninferior in the 9vHPV group compared with the 4vHPV group. Immunogenicity in males aged 16 through 26 years was compared with females of the same age group in a separate study. In both females and males, >99% seroconverted to all nine HPV vaccine types, and GMTs in males were noninferior to those in females (4). The immunogenicity of concomitant and nonconcomitant administration of 9vHPV with quadrivalent meningococcal conjugate vaccine (Menactra, MenACWY-D) and tetanus, diphtheria, acellular pertussis vaccine (Adacel, Tdap) was evaluated. The GMTs were noninferior for all nine HPV vaccine types in the co-administered group (all p<0.001). For Menactra, the noninferiority criterion was met for all four serogroups, and for Adacel, for diphtheria, tetanus, and all four pertussis antigens. Safety has been evaluated in approximately 15,000 subjects in the 9vHPV clinical development program; approximately 13,000 subjects in six studies were included in the initial application submitted to FDA (2). The vaccine was well-tolerated, and most adverse events were injection site-related pain, swelling, and erythema that were mild to moderate in intensity. The safety profiles were similar in 4vHPV and 9vHPV vaccinees. Among females aged 9 through 26 years, 9vHPV recipients had more injection-site adverse events, including swelling (40.3% in the 9vHPV group compared with 29.1% in the 4vHPV group) and erythema (34.0% in the 9vHPV group compared with 25.8% in the 4vHPV group). Males had fewer injection site adverse events. In males aged 9 through 15 years, injection site swelling and erythema in 9vHPV recipients occurred in 26.9% and 24.9%, respectively. Rates of injection-site swelling and erythema both increased following each successive dose of 9vHPV. Health Impact and Cost Effectiveness Introduction of 9vHPV in both males and females was cost-saving when compared with 4vHPV for both sexes in a cost-effectiveness model that assumed 9vHPV cost $13 more per dose than 4vHPV. Cost-effectiveness ratios for 9vHPV remained favorable compared with 4vHPV (9vHPV was cost-saving in most scenarios, and the cost per quality-adjusted life year gained did not exceed $25,000 in any scenario) when varying assumptions about HPV natural history, cervical cancer screening, vaccine coverage, vaccine duration of protection, and health care costs, but were sensitive to 9vHPV cost assumptions (17). Because the additional five types in 9vHPV account for a higher proportion of HPV-associated cancers in females compared with males and cause cervical precancers, the additional protection from 9vHPV will mostly benefit females. Recommendations for Use of HPV Vaccines ACIP recommends that routine HPV vaccination be initiated at age 11 or 12 years. The vaccination series can be started beginning at age 9 years. Vaccination is also recommended for females aged 13 through 26 years and for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series (1). Males aged 22 through 26 years may be vaccinated.† Vaccination of females is recommended with 2vHPV, 4vHPV (as long as this formulation is available), or 9vHPV. Vaccination of males is recommended with 4vHPV (as long as this formulation is available) or 9vHPV. 2vHPV, 4vHPV, and 9vHPV all protect against HPV 16 and 18, types that cause about 66% of cervical cancers and the majority of other HPV-attributable cancers in the United States (1,12). 9vHPV targets five additional cancer causing types, which account for about 15% of cervical cancers (12). 4vHPV and 9vHPV also protect against HPV 6 and 11, types that cause anogenital warts. What is currently recommended? The Advisory Committee on Immunization Practices (ACIP) recommends routine HPV vaccination at age 11 or 12 years. The vaccination series can be started beginning at age 9 years. Vaccination is also recommended for females aged 13 through 26 years and for males aged 13 through 21 years who have not been vaccinated previously or who have not completed the 3-dose series. Males aged 22 through 26 years may be vaccinated. ACIP recommends vaccination of men who have sex with men and immunocompromised persons through age 26 years if not vaccinated previously. Why are the recommendations being updated now? 9-valent HPV vaccine (9vHPV) was approved by the Food and Drug Administration on December 10, 2014. This vaccine targets HPV types 6, 11, 16, and 18, the types targeted by the quadrivalent HPV vaccine (4vHPV), as well as five additional types, HPV types 31, 33, 45, 52, and 58. ACIP reviewed results of a randomized trial among approximately 14,000 females aged 16 through 26 years that showed noninferior immunogenicity for the types shared by 4vHPV and 9vHPV and high efficacy for the five additional types. Other trials in the 9vHPV clinical development program included studies that compared antibody responses across age groups and females and males and concomitant vaccination studies. The evidence supporting 9vHPV vaccination was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework and determined to be type 2 (moderate level of evidence) among females and 3 (low level of evidence) among males; the recommendation was designated as a Category A recommendation (recommendation for all persons in an age- or risk-factor–based group). What are the new recommendations? 9vHPV, 4vHPV or 2vHPV can be used for routine vaccination of females aged 11 or 12 years and females through age 26 years who have not been vaccinated previously or who have not completed the 3-dose series. 9vHPV or 4vHPV can be used for routine vaccination of males aged 11 or 12 years and males through age 21 years who have not been vaccinated previously or who have not completed the 3-dose series. ACIP recommends either 9vHPV or 4vHPV vaccination for men who have sex with men and immunocompromised persons (including those with HIV infection) through age 26 years if not vaccinated previously. Administration 2vHPV, 4vHPV, and 9vHPV are each administered in a 3-dose schedule. The second dose is administered at least 1 to 2 months after the first dose, and the third dose at least 6 months after the first dose§ (1). If the vaccine schedule is interrupted, the vaccination series does not need to be restarted. If vaccination providers do not know or do not have available the HPV vaccine product previously administered, or are in settings transitioning to 9vHPV, any available HPV vaccine product may be used to continue or complete the series for females for protection against HPV 16 and 18; 9vHPV or 4vHPV may be used to continue or complete the series for males. There are no data on efficacy of fewer than 3 doses of 9vHPV. Special Populations HPV vaccination is recommended through age 26 years for men who have sex with men and for immunocompromised persons (including those with HIV infection) who have not been vaccinated previously or have not completed the 3-dose series. Precautions and Contraindications HPV vaccines are contraindicated for persons with a history of immediate hypersensitivity to any vaccine component. 4vHPV and 9vHPV are contraindicated for persons with a history of immediate hypersensitivity to yeast. 2vHPV should not be used in persons with anaphylactic latex allergy. HPV vaccines are not recommended for use in pregnant women (1). If a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose series should be delayed until completion of pregnancy. Pregnancy testing is not needed before vaccination. If a vaccine dose has been administered during pregnancy, no intervention is needed. A new pregnancy registry has been established for 9vHPV (2). Pregnancy registries for 4vHPV and 2vHPV have been closed with concurrence from FDA (1,18). Exposure during pregnancy can be reported to the respective manufacturer.¶ Patients and health care providers can report an exposure to HPV vaccine during pregnancy to the Vaccine Adverse Event Reporting System (VAERS). Adverse events occurring after administration of any vaccine should be reported to VAERS. Additional information about VAERS is available by telephone (1–800–822–7967) or online at http://vaers.hhs.gov. Cervical Cancer Screening Cervical cancer screening is recommended beginning at age 21 years and continuing through age 65 years for both vaccinated and unvaccinated women (19,20). Recommendations will continue to be evaluated as further postlicensure monitoring data become available. Future Policy Issues A clinical trial is ongoing to assess alternative dosing schedules of 9vHPV. ACIP will formally review the results as data become available. HPV vaccination should not be delayed pending availability of 9vHPV or of future clinical trial data.
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            Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines

            Introduction On October 20, 2017, Zoster Vaccine Recombinant, Adjuvanted (Shingrix, GlaxoSmithKline, [GSK] Research Triangle Park, North Carolina), a 2-dose, subunit vaccine containing recombinant glycoprotein E in combination with a novel adjuvant (AS01B), was approved by the Food and Drug Administration for the prevention of herpes zoster in adults aged ≥50 years. The vaccine consists of 2 doses (0.5 mL each), administered intramuscularly, 2–6 months apart ( 1 ). On October 25, 2017, the Advisory Committee on Immunization Practices (ACIP) recommended the recombinant zoster vaccine (RZV) for use in immunocompetent adults aged ≥50 years. Herpes zoster is a localized, usually painful, cutaneous eruption resulting from reactivation of latent varicella zoster virus (VZV). Herpes zoster is common: approximately one million cases occur each year in the United States ( 2 ). The incidence increases with age, from five cases per 1,000 population in adults aged 50–59 years to 11 cases per 1,000 population in persons aged ≥80 years ( 2 ). Postherpetic neuralgia, commonly defined as persistent pain for at least 90 days following the resolution of the herpes zoster rash, is the most common complication and occurs in 10%–13% of herpes zoster cases in persons aged >50 years ( 3 , 4 ). Among persons with herpes zoster, the risk for developing postherpetic neuralgia also increases with age ( 3 – 5 ). Zoster Vaccine Live (ZVL) (Zostavax, Merck and Co., Inc., Whitehouse Station, New Jersey), a 1-dose live attenuated strain of VZV, is licensed for the prevention of herpes zoster in immunocompetent adults aged ≥50 years and is recommended by the ACIP for use in immunocompetent adults aged ≥60 years ( 6 ). Since licensure, vaccine coverage has increased each year, and by 2016, 33% of adults aged ≥60 years reported receipt of the vaccine (CDC, provisional unpublished data). ACIP considered use of RZV, as well as existing recommendations, to develop vaccination policy which would be safe and reduce disease burden. This report serves as a supplement to the 2008 Prevention of Herpes Zoster Recommendations of ACIP for the use of ZVL in adults aged ≥60 years and subsequent updates ( 6 – 8 ); it outlines recent ACIP recommendations as well as guidance for use of RZV and ZVL in adults. Methods From March 2015 to October 2017, the ACIP Herpes Zoster Vaccines Work Group (Work Group; see acknowledgments for members and their affiliations) participated in monthly or bimonthly teleconferences to review herpes zoster epidemiology and the evidence for the efficacy, safety, and programmatic factors of RZV and ZVL. According to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the Work Group defined critical and important outcomes, conducted a systematic review of the evidence, and subsequently reviewed and discussed findings and evidence quality (https://www.cdc.gov/vaccines/acip/recs/grade/) ( 9 ). A cost effectiveness analysis comparing RZV, ZVL, or no vaccine was conducted by CDC from a societal perspective, using an analytic horizon of time of vaccination through the end of life. Model inputs were based on published literature where available and relied on unpublished data and Work Group expert opinion when necessary. It was modeled that ZVL effectiveness against herpes zoster would wane to zero 4–12 years following vaccination, depending on age at vaccination ( 4 , 10 – 13 ). In the absence of long-term effectiveness data, it was modeled that RZV effectiveness in adults aged 50–69 years or ≥70 years would wane to zero 19 years following vaccination based on the rate of waning observed during the first 4 years of clinical trials as well as expert opinion ( 13 – 15 ). Economic analyses were also conducted for RZV in cohorts previously vaccinated with ZVL. In keeping with CDC practice ( 16 , 17 ), the purpose of the economic analysis was to model the proposed recommendation; therefore, full adherence to a 2-dose RZV regime was assumed in baseline models. Lower rates of 2-dose adherence were evaluated in sensitivity analyses. Since 2015, RZV was discussed at five ACIP meetings. In addition to the aforementioned data, several independent health economic studies ( 18 , 19 ), (Merck, unpublished data, 2017), as well as immunogenicity data were presented. Long-term immunogenicity of RZV ( 20 ) and immunogenicity and safety of RZV in ZVL recipients ( 21 ) were considered, with recognition that there are no standard immunologic correlates of protection for prevention of herpes zoster. At the October 2017 meeting, three proposed recommendations were presented to the committee, and, after a public comment period, were approved by the voting ACIP members as follows: 1) RZV is recommended for immunocompetent adults aged ≥50 years (14 voted in favor, 1 opposed*), 2) RZV is recommended for immunocompetent adults previously vaccinated with ZVL (12 voted in favor, 3 opposed), and 3) RZV is preferred over ZVL (8 voted in favor, 7 opposed). This report summarizes the data considered, the quality of evidence, and rationale for recommendations. Summary of Findings As a result of the GRADE process, key outcomes were designated as critical (prevention of herpes zoster and postherpetic neuralgia, serious adverse events following vaccination) or important (duration of protection, reactogenicity). All outcomes were considered for both RZV and ZVL compared with no vaccination. There were no clinical studies that compared the vaccines directly with one another (head-to-head). Supporting evidence for the Work Group’s findings is available online (https://www.cdc.gov/vaccines/acip/recs/grade/herpes-zoster.html) ( 22 ). Recombinant Zoster Vaccine (RZV). Efficacy of RZV was evaluated in a two-part, phase III multicenter clinical trial which enrolled >30,000 participants, who were randomized 1:1 to receive vaccine or saline placebo ( 14 , 15 ). The median follow-up time was 3.2 years for Zoster Efficacy Study in Adults 50 Years of Age or Older (ZOE-50) ( 14 ), and 3.7 years for Zoster Efficacy Study in Adults 70 Years of Age or Older (ZOE-70) ( 15 ). The efficacy for the prevention of herpes zoster was 96.6% (95% confidence interval [CI] = 89.6–99.3) in persons aged 50–59 years and 97.4% (95% CI = 90.1–99.7) in persons aged 60–69 years ( 14 ). Using pooled data from both study arms, vaccine efficacy was 91.3% (95% CI = 86.8–94.5) in participants aged ≥70 years ( 15 ). Vaccine efficacy in the first year after vaccination was 97.6% (95% CI = 90.9–99.8) and was 84.7% (95% CI = 69.0–93.4) or higher for the remaining 3 years of the study in persons aged ≥70 years. Efficacy for prevention of postherpetic neuralgia was 91.2% (95% CI = 75.9–97.7) in adults aged ≥50 years and 88.8% (95% CI = 68.7–97.1) in those aged ≥70 years ( 15 ). Serious adverse events (an undesirable experience associated with the vaccine that results in death, hospitalization, disability or requires medical or surgical intervention to prevent a serious outcome) were examined in eight studies sponsored by GSK, which included 29,965 subjects (15,264 RZV recipients) ( 22 ). Overall, rates of serious adverse events over the study periods were similar in the RZV and placebo groups. Injection-site and systemic grade 3 solicited adverse events (reactions related to vaccination which were severe enough to prevent normal activities) were actively surveyed in eight studies involving 10,590 subjects ( 22 ). Among the subset of subjects completing the 7-day diary card for reactogenicity in phase III clinical trials (9,936), 16.5% of vaccine recipients reported any grade 3 adverse event compared with 3.1% of placebo recipients ( 14 , 15 ). Grade 3 injection-site reactions (pain, redness, and swelling) were reported by 9.4% of vaccine recipients, compared with 0.3% of placebo recipients and grade 3 solicited systemic events (myalgia, fatigue, headache, shivering, fever, and gastrointestinal symptoms) were reported by 10.8% of vaccine recipients and 2.4% of placebo recipients ( 14 , 15 ). Whereas there were no differences in the proportions of local grade 3 reactions between dose 1 and dose 2, systemic grade 3 reactions were reported more frequently after dose 2 ( 1 ). Overall, the most common solicited adverse reactions (grade 1–3) were pain (78%), myalgia (45%), and fatigue (45%) ( 1 ). Zoster Vaccine Live (ZVL). Two randomized clinical trials and seven observational studies were reviewed to evaluate the performance of a single dose of ZVL in preventing herpes zoster ( 22 ). A randomized clinical trial in persons aged 50–59 years found that the efficacy was 70% (95% CI = 54–81) (median follow-up time was 1.3 years) ( 12 ). A randomized trial in persons aged ≥60 years found that the efficacy was 64% (95% CI = 56–71) in persons aged 60–69 years and 38% (95% CI = 25–48) in persons aged ≥70 (median follow-up time was 3.1 years) ( 4 ). Estimates from observational studies and randomized controlled trials (RCTs) are consistent; observational estimates are within the 95% CI of the RCT estimates ( 22 ). The duration of protection has been studied out to 11 years, including the first 4 years of the RCT and then follow-on, nonblinded studies which used a modeled control group from years 7–11 ( 4 , 10 , 11 ). Shorter follow-up periods have been evaluated in observational studies using administrative health data ( 22 ). Studies concur that there is a substantial decrease in effectiveness following the first year after receipt of ZVL, and, by 6 years postvaccination, vaccine effectiveness against herpes zoster is <35% ( 10 , 23 – 25 ). During years 7–8 postvaccination, observational study estimates of effectiveness ranged from 21%–32% ( 23 , 24 ). In the longest study of ZVL, estimates of effectiveness were no longer statistically significant 9–11 years postvaccination ( 11 ). In a phase III clinical trial, vaccine efficacy against post herpetic neuralgia was 65.7% (95% CI = 20.4–86.7) in persons aged 60–69 years and 66.8% (95% CI = 43.3–81.3) in participants aged ≥70 years (median follow-up of 3.1 years) ( 4 ); these estimates are consistent with estimates from observational studies ( 22 ). Notably, in observational studies, vaccine effectiveness against postherpetic neuralgia was longer-lasting than effectiveness against herpes zoster itself ( 23 , 26 ). Serious adverse events related to ZVL were examined in eight high quality RCTs, 13 RCTs with limitations, and an additional seven observational studies ( 22 ). Overall, serious adverse events occurred at similar rates in vaccinated and placebo groups. Whereas injection site reactions were reported in 48% of vaccine recipients and 17% of placebo recipients in phase III clinical trials, post hoc analysis indicates that no more than 0.9% of vaccine recipients reported any given injection site symptom as grade 3 ( 22 ). In addition, in rare instances, ZVL vaccine strain has been documented to cause disseminated rash as well as herpes zoster in immunocompetent recipients ( 22 , 27 ), and life-threatening and fatal complications in immunocompromised recipients ( 28 , 29 ). Cost effectiveness. The CDC analysis was conducted from a societal perspective over a lifetime. It estimated that vaccination with RZV, compared with no vaccination, cost $31,000 per quality adjusted life year (QALY), on average, for immunocompetent adults aged ≥50 years. The numbers of persons needed to be vaccinated with RZV to prevent one case of herpes zoster and one case of postherpetic neuralgia are 11–17 and 70–187, respectively. Estimates of costs per QALY for vaccination with RZV 8 weeks following ZVL (estimated by immediate revaccination in the model) ranged from $15,000 per QALY in persons aged 80–89 years to $117,000 per QALY for persons aged 50–59 years. Under most assumptions, vaccination with RZV prevented more disease at lower overall costs than did vaccination with ZVL. In probabilistic sensitivity analyses, 73.5% 2-dose completion (range = 38.8%–96.3%) coupled with 1-dose initial effectiveness estimates of 90% and 69% were applied, and RZV remained the most cost-effective strategy ( 13 ). ACIP also reviewed independent cost-effectiveness analyses by an academic group ( 18 ), GSK ( 19 ), and Merck (Merck, unpublished data, 2017). The academic group estimated RZV costs per QALY of $30,000 when vaccination occurred at age 60 years. The GSK model estimated RZV costs per QALY of $12,000, on average, for recipients aged ≥60 years. Although analytic approaches and model inputs differed, both groups found that RZV was more cost effective than ZVL. Merck modeled vaccination at age ≥60 years and estimated $107,000 per QALY for RZV and $83,000 per QALY for ZVL, with ZVL as the most cost-effective vaccine in most scenarios. Summary of the Quality of Evidence Across Outcomes The body of evidence for benefits of RZV (prevention of herpes zoster and postherpetic neuralgia and duration of protection against herpes zoster) was primarily informed by one high quality RCT that studied vaccine efficacy through 4 years postvaccination. The GRADE evidence type was judged as 1, the strongest level of evidence ( 22 ). The evidence for possible harms (serious adverse events and reactogenicity) was reported in the same RCT and was consistent across additional smaller, less rigorous studies. Overall, the estimates of possible harms were supported by GRADE evidence type 1 ( 22 ). The body of evidence for benefits of ZVL (prevention of herpes zoster and postherpetic neuralgia, and duration of protection against herpes zoster) was large, including a high quality prelicensure RCT as well as a postlicensure RCT and observational studies of effectiveness. The level of vaccine effectiveness for the prevention of herpes zoster and postherpetic neuralgia was supported by GRADE evidence type 1 ( 22 ). The duration of protection beyond 4 years was supported by GRADE evidence type 2 because the studies lacked blinding, and beyond 6 years, lacked randomization and a true control group. The evidence for possible harms of ZVL (serious adverse events and reactogenicity) was supported by GRADE evidence type 1 from multiple RCTs and supported by observational studies and a decade of experience ( 22 , 29 ). Rationale RZV use in immunocompetent adults aged ≥50 years. With high efficacy among adults aged ≥50 years, and modest waning of protection over 4 years following vaccination, RZV has the potential to prevent substantial herpes zoster disease burden. Vaccinating adults starting at age 50 will prevent disease incidence in midlife, and the vaccine will likely continue to provide substantial protection beyond 4 years as recipients age. RZV use in immunocompetent adults who previously received ZVL. In separate clinical trials, RZV estimates of efficacy against herpes zoster were higher than ZVL estimates in all age categories. The difference in efficacy between the two vaccines was most pronounced among recipients aged ≥70 years. Studies have shown that ZVL effectiveness wanes substantially over time, leaving recipients with reduced protection against herpes zoster. RZV elicited similar safety, reactogenicity, and immunogenicity profiles regardless of prior ZVL receipt; therefore, ZVL recipients will likely benefit from vaccination with RZV. Preferential use of RZV. In separate clinical trials, for all age categories, RZV estimates of efficacy against herpes zoster were higher than those for ZVL. Estimates of efficacy against postherpetic neuralgia are also higher for RZV than for ZVL; however, CIs overlap. ZVL efficacy wanes substantially during the 4 years following receipt. As a result of higher and more long-lasting efficacy, RZV is estimated to prevent more herpes zoster and postherpetic neuralgia compared with ZVL. ACIP acknowledged that several aspects of RZV performance will be further elucidated postlicensure, including the possibility of a rare adverse event related to the vaccine, the long-term duration of protection, the adherence to the 2-dose schedule, and the effectiveness and duration of protection of 1 dose of RZV. Some ACIP members preferred to recommend both vaccines with no preference until real-world data could be accrued, including head-to-head studies. The majority of ACIP members voted to recommend RZV preferentially (Box). BOX Recommendations for the use of herpes zoster vaccines In October 2017, the Advisory Committee on Immunization Practices (ACIP) made the following three recommendations: Recombinant zoster vaccine (RZV) is recommended for the prevention of herpes zoster and related complications for immunocompetent adults aged ≥50 years. RZV is recommended for the prevention of herpes zoster and related complications for immunocompetent adults who previously received zoster vaccine live (ZVL). RZV is preferred over ZVL for the prevention of herpes zoster and related complications. These recommendations serve as a supplement to the existing recommendations for the use of ZVL in immunocompetent adults aged ≥60 years. Clinical Guidance General use. RZV may be used in adults aged ≥50 years, irrespective of prior receipt of varicella vaccine or ZVL, and does not require screening for a history of chickenpox (varicella). ZVL remains a recommended vaccine for prevention of herpes zoster in immunocompetent adults aged ≥60 years ( 6 ). Care should be taken not to confuse ZVL, which is stored in the freezer and administered subcutaneously, with RZV, which is stored in the refrigerator and administered intramuscularly. Dosing schedule. Following the first dose of RZV, the second dose should be given 2–6 months later ( 1 ). The vaccine series need not be restarted if more than 6 months have elapsed since the first dose; however, the efficacy of alternative dosing regimens has not been evaluated, data regarding the safety of alternative regimens are limited ( 30 ), and individuals might remain at risk for herpes zoster during a longer than recommended interval between doses 1 and 2. If the second dose of RZV is given less than 4 weeks after the first, the second dose should be repeated. Two doses of the vaccine are necessary regardless of prior history of herpes zoster or prior receipt of ZVL. Timing of RZV for persons previously vaccinated with ZVL. Age and time since receipt of ZVL may be considered to determine when to vaccinate with RZV. Studies examined the safety and immunogenicity of RZV vaccination administered ≥5 years after ZVL ( 21 ); shorter intervals have not been studied. However, there are no data or theoretical concerns to indicate that RZV would be less safe or less effective when administered at an interval of <5 years. Clinical trials indicated lower efficacy of ZVL in adults aged ≥70 years; therefore, a shorter interval may be considered based on the recipient’s age when ZVL was administered. Based on expert opinion, RZV should not be given <2 months after receipt of ZVL. Coadministration with other vaccines. CDC’s general best practice guidelines for immunization advise that recombinant and adjuvanted vaccines, such as RZV, can be administered concomitantly, at different anatomic sites, with other adult vaccines ( 31 ). Concomitant administration of RZV with Fluarix Quadrivalent (influenza vaccine) (QIV) has been studied, and there was no evidence for interference in the immune response to either vaccine or safety concerns ( 32 ). Evaluation of coadministration of RZV with 23-valent pneumococcal polysaccharide vaccine (PPSV23, Pneumovax23) and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed (Tdap, Boostrix) is ongoing. The safety and efficacy of administration of two adjuvanted vaccines (e.g., RZV and adjuvanted influenza vaccine [Fluad]), either concomitantly or at other intervals, have not been evaluated. Counseling for reactogenicity. Before vaccination, providers should counsel RZV recipients about expected systemic and local reactogenicity. Reactions to the first dose did not strongly predict reactions to the second dose ( 33 ); vaccine recipients should be encouraged to complete the series even if they experienced a grade 1–3 reaction to the first dose of RZV. The impact of prophylactic analgesics in conjunction with RZV has not been studied. Special Populations Persons with a history of herpes zoster. Herpes zoster can recur. Adults with a history of herpes zoster should receive RZV. If a patient is experiencing an episode of herpes zoster, vaccination should be delayed until the acute stage of the illness is over and symptoms abate. Studies of safety and immunogenicity of RZV in this population are ongoing. Persons with chronic medical conditions. Adults with chronic medical conditions (e.g., chronic renal failure, diabetes mellitus, rheumatoid arthritis, and chronic pulmonary disease) should receive RZV. Immunocompromised persons. As with ZVL, the ACIP recommends the use of RZV in persons taking low-dose immunosuppressive therapy (e.g., <20 mg/day of prednisone or equivalent or using inhaled or topical steroids) and persons anticipating immunosuppression or who have recovered from an immunocompromising illness ( 6 ). Whereas RZV is licensed for all persons aged ≥50 years, immunocompromised persons and those on moderate to high doses of immunosuppressive therapy were excluded from the efficacy studies (ZOE-50 and ZOE-70), and thus, ACIP has not made recommendations regarding the use of RZV in these patients; this topic is anticipated to be discussed at upcoming ACIP meetings as additional data become available. Persons known to be VZV negative. Screening for a history of varicella (either verbally or via laboratory serology) before vaccination for herpes zoster is not recommended. However, in persons known to be VZV negative via serologic testing, ACIP guidelines for varicella vaccination should be followed. RZV has not been evaluated in persons who are VZV seronegative and the vaccine is not indicated for the prevention of chickenpox (varicella). Contraindication Allergy. RZV should not be administered to persons with a history of severe allergic reaction, such as anaphylaxis, to any component of this vaccine. Precautions Current herpes zoster infection. RZV is not a treatment for herpes zoster or postherpetic neuralgia and should not be administered during an acute episode of herpes zoster. Pregnancy and breastfeeding. There are no available data to establish whether RZV is safe in pregnant or lactating women and there is currently no ACIP recommendation for RZV use in this population. Consider delaying vaccination with RZV in such circumstances. Reporting of Vaccine Adverse Reactions Adverse events that occur in a patient following vaccination can be reported to the Vaccine Adverse Events Reporting System (VAERS). Reporting is encouraged for any clinically significant adverse event even if it is uncertain whether the vaccine caused the event. Information on how to submit a report to VAERS is available at https://vaers.hhs.gov/index.html or by telephone at 1–800–822–7967. Future Research and Monitoring Priorities Studies of safety, immunogenicity, and efficacy of herpes zoster vaccines in defined immunocompromised populations are ongoing. ACIP will consider these data as they become available and revise recommendations accordingly. In addition, CDC will monitor coverage of RZV and adherence to the 2-dose schedule. Short-term and long-term effectiveness of RZV will be assessed through longitudinal studies of clinical trial participants as well as through observational studies. As with all new vaccines, CDC will monitor adverse events following immunization through VAERS and the Vaccine Safety Datalink. Additional post-marketing safety monitoring will include studies conducted by GSK and reported to the FDA. Monitoring RZV is particularly important given the vaccine’s novel adjuvant and its high reactogenicity and immunogenicity.
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              Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP).

              This report summarizes the epidemiology of human papillomavirus (HPV) and associated diseases, describes the licensed HPV vaccines, provides updated data from clinical trials and postlicensure safety studies, and compiles recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) for use of HPV vaccines. Persistent infection with oncogenic HPV types can cause cervical cancer in women as well as other anogenital and oropharyngeal cancers in women and men. HPV also causes genital warts. Two HPV vaccines are licensed in the United States. Both are composed of type-specific HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein using recombinant DNA technology produces noninfectious virus-like particles (VLPs). Quadrivalent HPV vaccine (HPV4) contains four HPV type-specific VLPs prepared from the L1 proteins of HPV 6, 11, 16, and 18. Bivalent HPV vaccine (HPV2) contains two HPV type-specific VLPs prepared from the L1 proteins of HPV 16 and 18. Both vaccines are administered in a 3-dose series. ACIP recommends routine vaccination with HPV4 or HPV2 for females aged 11 or 12 years and with HPV4 for males aged 11 or 12 years. Vaccination also is recommended for females aged 13 through 26 years and for males aged 13 through 21 years who were not vaccinated previously. Males aged 22 through 26 years may be vaccinated. ACIP recommends vaccination of men who have sex with men and immunocompromised persons (including those with HIV infection) through age 26 years if not previously vaccinated. As a compendium of all current recommendations for use of HPV vaccines, information in this report is intended for use by clinicians, vaccination providers, public health officials, and immunization program personnel as a resource. ACIP recommendations are reviewed periodically and are revised as indicated when new information and data become available.
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                Author and article information

                Journal
                MMWR Morb Mortal Wkly Rep
                MMWR Morb. Mortal. Wkly. Rep
                WR
                Morbidity and Mortality Weekly Report
                Centers for Disease Control and Prevention
                0149-2195
                1545-861X
                08 February 2019
                08 February 2019
                : 68
                : 5
                : 115-118
                Affiliations
                Immunization Services Division, National Center for Immunization and Respiratory Diseases, CDC; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
                Author notes
                Corresponding author: David K. Kim, ddk5@ 123456cdc.gov , 404-639-0969.
                Article
                mm6805a5
                10.15585/mmwr.mm6805a5
                6366679
                30730868
                0d1e6a77-9c30-49e3-b4a9-0be3a016f380

                All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated.

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