Vaccine Update Roger D Lovell, MD Infectious Disease Consultants 1270 Prince Avenue – Suite 301 Athens, GA 30606 770-670-7245 Financial Disclosures

None Nada Niet Nein Nahi Lo La Topics

• Human Papilloma Virus (HPV) Vaccine

• Shingles (VZV) Vaccine

• Pneumococcal Vaccines

• Seasonal Influenza Vaccine HPV Vaccine

• Background Information • HPV is a sexually transmitted virus causing anogenital and oropharyngeal lesions • Males and females • Persistent infection with high-risk genotypes leads to cancer • HPV 16, 18 – causes 70% of cervical cancers • HPV 31, 33, 45, 52, 58 – another 20% of cervical cancers • HPV 16 and HPV 18 – 90% of anal cancers • Also high proportion of oropharyngeal cancer, vulvar cancer, vaginal cancer, penile cancer

• HPV 6 and HPV 11 – 90% of anogenital warts HPV Vaccine

• Background Information • Natural History HPV Vaccine

• Background Information HPV Vaccine

• Background Information • Burden HPV Vaccine

• Background Information – expand vaccine???? HPV Vaccine

• Background Information • Available Vaccines – prophylactic vaccines • Quadrivalent HPV vaccine (Gardasil) – HPV 6, 11, 6, 18 • 9-valent vaccine (Gardasil-9) – HPV 6, 11, 16, 18; also 31, 33, 45, 52, 58 • Bivalent vaccine (Cervarix) – HPV 16, 18

• Vaccination provides direct benefit for females by protecting against persistent HPV infections that lead to cancer – best studied with cervical cancers • HPV 16 and 18; HPV 31, 33, 45, 52, 58 • And decrease in genital warts -- HPV 6 and 11 HPV Vaccine

• Vaccine Effectiveness – modeling • If vaccinate all 12 year old females in US, each year you would • Prevent 200,000 HPV infections • Prevent 100,000 abnormal PAP smears • Prevent 3,300 cases of cervical cancer • And provide herd immunity for males – decreased genital warts

• HPV vaccination of males – overall burden less than in females • Direct benefit for protecting against cancer • HPV 16 and 18 – 90% of anal cancers • And most oral/penile cancers • Prevents anogenital wart – HPV 6 and 11 • Vaccinating both more beneficial than vaccinating females only HPV Vaccine

• Vaccine schedule • Females – between 11 and 12 years old; as early as 9 years old • Catch-up vaccine between 13-26 years old (if not previously vaccinated or did not complete the series previously)

• Males - between 11 and 12 years old; as early as 9 years old • Catch-up vaccine between 13-21 years old (if not previously vaccinated or did not complete the series previously)

• Age 22-26 • MSM • Immune suppressed/HIV HPV Vaccine

• Vaccine schedule • Above 26 years - ???45 years old • Increased likelihood of previous exposure to HPV • Reduces cost effectiveness • Reduces potential benefit

• Exceptions – no previous sexual activity; lifelong sexual monogomany

• May not be covered by insurance

• Timing – before sexual activity • Current vaccines do no treat or aid in recovery from existing lesions • There are treatment vaccines being developed • Having warts or abnormal PAP or previous infection is not a contraindication HPV Vaccine

• Vaccine schedule • Initial dosing/timing • If first dose before age 15, two doses needed – time 0 and then second dose between 6 - 12 months • If second dose given too early ---- the second dose should be repeated 12 weeks after first dose and at least 5 months after the first dose

• If first dose 15 years or older, three doses are needed at time 0 and between 1-2 months, and then at 6 months • If any dose given too early, it should be repeated once the recommended interval after the most recent dose has passed

• Immunocompromised – Three doses at time 0, then between 1-2 months, and then 6 months after the first dose

• Missed doses – just pick up where you were HPV Vaccine

• Vaccine schedule • Can be co-administered with any other age appropriate vaccine – different site

• No pre-vaccine testing needed

• No need to measure post-vaccine antibodies

• No reason for re-vaccination or booster HPV Vaccine

• Other stuff • Pregnancy and Breastfeeding • If vaccinated inadvertently during pregnancy, resume after delivery • Available evidence that fetus/baby are safe – no increased risk with pregnancy has been observed

• Lactating – safe

• Pre-existing HPV infection/disease • Infection types may not be the serotypes on the vaccine • No effect on pre-existing infection progression HPV Vaccine

• Other stuff • Immunosuppressed • Transplants • HIV • Hypogammaglobulinemia • T cell defects (DiGeorge’s) • Malignant cancers • Autoimmune diseases • Immunosuppressive therapies

• Three vaccine schedule – 0, 1-2, 6 months

• Some data – less robust immune response; less duration HPV Vaccine

• Immunogenicity and Efficacy • Seroconversion rates – 93-100% females • Males – 99-100% • Titers higher in those vaccinated younger • Cutoff for protection not known

• Efficacy • Cerivcal, Vaginal, Vulvar disease • Three vaccine trials • 9-valent HPV vaccine – 97% effective in preventing CIN2 or more severe disease in HPV naïve populations

• Also effective in preventing subsequent infection and disease HPV Vaccine

• Efficacy • Anal disease – most HPV 16 ad 18 • Less data • Study in MSM ages 16-26, efficacy in preventing AIN due to the HPV serotypes in the vaccine was 78% in HPV naïve populations • 50% effective overall

• Oral disease • Indirect data from trial preventing cervical cancer • Fewer oral HPV lesions (HPV 16 and 18) 4 years later • Vaccine efficacy 93% HPV Vaccine

• Efficacy • Anogenital warts – HPV 6 ad 11 • 90-100% effective preventing warts due to HPV serotypes in the vaccine

• Others • Respiratory papillomatosis – HPV 6 and 11 • Australia – national vaccination program • 8-fold reduction • ALL cases occurred in offspring of unvaccinated females

• Duration of protection – unknown; at least 10 years • Data to come HPV Vaccine

• Safety • From trials and post-licensure data • Mild site reactions • Post vaccine syncope • Others – nausea, vomiting, fatigue, weakness • No increased GBS compared to other vaccines/age groups • Others – association not established or known • VTE – all have had other risk factors for VTE • Anaphylaxis – risk 0.1/100,000 doses • MS/demyelinating syndromes • Larger studies have refuted (Swedish) HPV Vaccine

• Other • Concern for sexual disinhibition – studies do not support

• Vaccine use/coverage • Use in US has not been good; other nations have it part of national vaccine program – 60% use

• 100% of eligible males/females had healthcare contact during time of vaccine age indications

• Data from 2015, 63/50% received at least one dose (females/males); 42/28% completed the vaccine series HPV Vaccine Prevention of Shingles

• VZV • Primary infection – Chickenpox

• Reactivation – Shingles/Herpes Zoster

years

- per 1,000 person 1,000 per Prevention of Shingles

• VZV • Role of cell medicated immunity (CMI) • Controls latency and risk for reactivation • Decline in immunity with age • About 1/3 of adults over 55 have no protective T cell responses/immunity • Humoral immune response less important • Boosting of CMI • Household exposures • Zoster vaccination boosts CMI Prevention of Shingles

• Vaccines • Candidates – Age > 50 • Does not matter if had chickenpox • Not necessary to check titers • More than 96% who have lived in US > 30 years have serologic evidence of prior varicella • Not to be used to treat active shingles or prevent PHN from a case of active shingles • Options • Live attenuated vaccine contains 18,700 – 60,000 plaque-forming units of vaccine – Zostavax • Non-live recombinant glycoprotein E vaccine – Recombinant Zoster Vaccine (RZV) - Shingrix Prevention of Shingles

• Vaccines • Shingrix (RZV) • Provides greater immunity than live attenuated vaccine • Especially in those above the age of 60 • Less waning immunity than live attenuated vaccine • No benefit of preventing shingles from live vaccine after year 8 • But some benefit for prevention of PHN • Zostavax (ZVL) • Only a single injection • Lower side effect profile 1-3 days after vaccine • Systemic – myalgia, fatigue, HA, shivering, fever Prevention of Shingles

• Vaccine efficacy • No head-to-head comparison • Shingrix (RZV) – 2 trials • Age > 50 – reduced risk of shingles 97.2% • Age > 70 – reduced risk of shingles 90%

• Zostavax (ZVL) – multiple studies pre-release and post marketing data • Age > 60 – reduced shingles incidence by 51% • Better between ages of 60-69 • Slight decrease in pain and discomfort • Post-herpetic neuralgia reduced 67% (better above age 70) • Post release review – vaccinate 50 to protect 1 person Prevention of Shingles

• Other stuff • Both are approved for age > 50, BUT NOT part of ACIP recommendations until age 60 • Populations • If currently have shingles, when to vaccinate? • The current shingles will boost immunity – possibly wait a couple of years • Immune suppressed • No stringent data • Short-term versus long-term immunosuppression • If there is planned immunosuppression, vaccinate as soon as that is known – at least 4 weeks before • Low dose immunosuppressive therapy (Prednisone < 20 mg daily, Methotrexate < 0.4 mg/kg/day, Azathioprine < 3 mg/kg/day, 6-MP < 1.5 mg/kg/day • No issues • Bone marrow/lymph cancer, transplants, HIV with CD4 < 200, Biologic therapies – defer • Household contacts of immune suppressed • RZV preferred • Previously vaccinated with ZVL – re-vaccinate with RZV (at least 8 weeks later) Prevention of Shingles

• Vaccine administration • Shingrix (RZV) • 2 doses that are given 2-6 months apart • Delay in getting the second dose – no need to be restarted • If second dose given too early, repeat the second dose at the recommended time • Can be co-administered with other vaccines – different sites • Studies are being performed • Side effects – localized (9.4% prevent daily activities) and systemic (10.8% prevent daily activities) Prevention of Shingles

• Vaccine administration • Zostavax (ZVL) • Single injection • Separate other live vaccines by at least 28 days • Pneumovax and ZVL – CAN and SHOULD be given together – if indications exist • Side effects • Local – mid • Acute retinal necrosis/optic neuritis • Vaccine-associated zoster • NOT immune suppressed (Bone marrow/lymph cancer, transplants, HIV with CD4 < 200, Biologic therapies) • NOT pregnant • NO VZV-active antiviral agents from 24 hours before thru 14 days after the vaccine Pneumococcal vaccination

• Introduction – pneumococcal infections • Increased morbidity and mortality • Pneumonia, meningitis, and bacteremia • In those above 65 years old • Chronic lung disease • Heart failure • Functional/anatomic asplenia • Cochlear implants • All children

• Highest mortality incidence • Children < 2 • Compromised antibody response – organ transplants, HIV, Multiple myeloma, Chronic lymphocytic leukemia • Age > 65 • Highest mortality – Age > 65 – especially if have other co-morbidities Pneumococcal vaccination

• Vaccines • Based on capsule polysaccharides - >90 different types • Pneumococcal polysaccharide vaccine (PPSV; Pneumovax) • Serotype 1,2,3,4,5,6B,7F,8,9N,9V,10A, 11A,12F, 14,15B,17F,18C,19A,19F,20,22F,23F,33F • First marketed in 1970s – 14 serotypes • Augmented in 1983 – 23 serotypes – Pneumovax23 • Serotypes that caused ~ 60% of pneumococcal infections • Children > 2; adults • Pneumococcal conjugate vaccine (PCV; Prevnar) • Initially marketed in 2000 as PCV7 – 7 serotypes commonly causing disease in children • Universal vaccination of children in 2000 • Reduces pneumococcal carriage in nasopharynx • Pre-PCV vaccine – 65-70% of pneumococcal pneumonia in adults due to serotypes found in the vaccine; now – almost never • 2007 – replaced by PCV13 – same decline in serotype prevalence • Serotype 1,3,4,5,6A,6B,7F,9V,14,18C,19A,19F,23F Pneumococcal vaccination Pneumococcal vaccination

• Vaccines • Indications • For all adults > 65 • Younger patients with underlying conditions • 2012 – ACIP recommended sequential vaccination PCV13 and PPSV23 • Increased risk of serious pneumococcal infection • Anatomic/functional asplenia • HIV; hypogammaglobulinemia; immune compromised • CSF leak • Cochlear implant • Advanced kidney disease • 2013 – ACIP extends sequential vaccination to all adults > 65 • 2011 – FDA approved PCV13 for adults > 50 • 2016 – FDA approved 18 – 49 years old Pneumococcal vaccination

• Vaccine schedule • Age > 65 – Immunocompetent; not previously vaccinated • Give PCV13 followed by PPSV23 at least 1 year after the PCV13 • Age > 65 – immune/spleen factors • If PCV13 was given for any risk/immune issues, give PPSV23 at least 1 year after the PCV13 • If PPSV23 was administered for any risk factor before age 65, give PCV13 at least one year after the PPSV23 dose

• Age 19 – 64 with Chronic heart disease, Chronic lung disease, Chronic liver disease, Alcoholism, DM, Cigarette use • Give one dose PPSV23 • At age > 65, give one dose PCV13 (unless received for another reason in the past) • And, PPSV23 at least 1 year after the PCV13; AND at least 5 years after the prior PPSV23 Pneumococcal vaccination

• Vaccine schedule • Age 19 – 64 with the following immune risks/conditions • Immunodeficiency – T or B cell, Complement, Phagocyte • HIV • Anatomic/functional asplenia • Chronic renal failure/nephrotic syndrome • CSF leak • Cochlear Implant

• PCV13 followed by PPSV23 at least 8 weeks later • Then a second dose of PPSV23 at least 5 years after the first PPSV23 • At Age 65, administer another dose PPSV23 – 5 years after the prior PPSV23 • Some expert opinion, give PPSV23 every 5 years Pneumococcal vaccination

• Vaccines • PCV13 (Prevnar) and PPSV23 (Pneumovax) sequential vaccination • Adults any age with CSF leak, Cochlear implant, Functional/anatomic asplenia; hemoglobinopathies • Also, immunocompromised conditions, congenital/acquired immunodeficiency, complement deficiencies, phagocytic diseases (NOT CGD); HIV infection; generalized malignancy (also those receiving chemotherapy); blood cancers; organ transplant; long term immunosuppression (steroids; XRT); chronic renal failure; nephrotic syndrome • All adults > 65 • Those who have survived invasive pneumococcal infection – bacteremia or meningitis • NOT ACIP – but expert opinion Pneumococcal vaccination

• Vaccine schedule • Immune suppressed; chronic kidney disease; asplenia; CSF leak; cochlear implant • No previous vaccine • PCV13 and then PPSV23 at least 8 weeks later • If previous PPSV23 • Give a single dose PCV13 one year after the PPSV23 • Age > 65 • NO previous vaccine • PCV23 and then PPSV23 at least one year later • If prior PPSV23 • PCV13 and then PPSV23 at least 5 years after prior PPSV23 • For those who need PCV13 but have received prior doses of PPSV23 • PCV13 at least 1 year after the last PPSV23 vaccine • For those < 65 who require PPSV23 revaccination (immune suppressed) • PPSV23 should be given at least 8 weeks after PCV13 and at least 5 years after prior PPSV23 Pneumococcal vaccination

• Revaccination schedule • Immunocompetent 19 – 64 who received prior PPSV23 • PPSV23 revaccination at age 65 • Some expert opinion to revaccinate every 5 – 10 years – NOT ACIP; may not be covered • Immunocompromised 19 – 64 previously given both PCV13 and PPSV23 • PPSV23 5 years after the first PPSV23 • PPSV23 revaccinate at age 65 • Asplenia previously received PCV13 and PPSV23 • Revaccinate every 5 years – expert opinion • ACIP says first vaccine, then repeat in 5 years; then repeat at age 65

• Revaccination with PCV13 is NOT recommended for any patient • PCV13 NOT recommended for healthy adults 19 – 64 unless risk factor present Seasonal Influenza Vaccination

• Summary of 2017 – 2018 Influenza season • 2017-18 season was the first season to be classified as a high severity across all age groups (since classification started in 2003-04) • Influenza-like Illness (ILI) visits peaked at 7.5%, the highest percentage since the 2009 H1N1 flu pandemic, which peaked at 7.7% • Influenza-like illness (ILI) was at or above the national baseline for 19 weeks - one of the longest in recent years • The percentage of deaths attributed to pneumonia and influenza was at or above the epidemic threshold for 16 consecutive weeks • Nationally, mortality attributed to P&I exceeded 10.0% for four consecutive weeks, peaking at 10.8% during the week ending January 20, 2018. • 185 pediatric deaths reported to CDC during the 2017-2018 season • Approximately 80% of these deaths occurred in children who had not received a flu vaccination this season Seasonal Influenza Vaccination

• Summary of 2017 – 2018 Influenza season • Influenza A(H3N2) viruses predominated overall during the 2017-2018 season • Influenza B viruses became more commonly reported than influenza A viruses in early March 2018 through May 2018

• The overall vaccine effectiveness of the 2017-2018 flu vaccine against both influenza A and B viruses is estimated to be 40% • This means the flu vaccine reduced a person’s overall risk of having to seek medical care at a doctor’s office for flu illness by 40% • Protection by virus type and subtype • 25% against A(H3N2) • 65% against A(H1N1) • 49% against influenza B viruses

• 1.0% of viral isolates were resistant to antiviral meds Seasonal Influenza Vaccination

• Influenza vaccination • High risk for influenza-related complications • Age 6 – 59 months • Age > 50 • Pregnant – until 2 weeks postpartum • Chronic conditions • Pulmonary; cardiovascular (NOT HTN); renal, liver; hematologic; metabolic/diabetes; neurologic (brain/spinal cord, cerebral palsy, epilepsy, CVA, intellectual disability, developmental delay, muscular dystrophy, SCI) • Any immune suppression • Age 6 months – 18 years old receiving ASA-containing meds • Any resident of nursing home or chronic care facility • All Native Americans (including Alaskans) • BMI > 40 • Live with or care for those at high risk • Healthcare workers • Household contacts – Children < 59 months (especially children < 6 months) or adults > 50 years • Chronic conditions Seasonal Influenza Vaccination

• Influenza vaccination (Northern hemisphere) • 2018 – 2019 Seasonal Influenza Vaccine – ideally administer by the end of October • H1N1 - A/Michigan/45/2015 pdm09-like A virus • H3N2 – A/Singapore/INFIMH-16-00192016-like A virus • Not the same as in 2017-2018 vaccine • B – B/Colorado/06/2017-like B virus • Not the same as in 2017-2018 vaccine • B – B/Phuket/3073/2013-like B virus

• Antigenic drifts – minor changes in glycoproteins (hemagglutinin and neuraminidase) • H1, H2, H3; N1, N2 • H5; H7; H9 – rare; other species • Antigenic shifts – Major changes; pandemics • Influenza B – fewer changes Seasonal Influenza Vaccination

• Vaccine formulations • Standard trivalent/quadrivalent inactivated vaccine (Fuzone; Fluarix) – produced in embryonated eggs • High-dose trivalent inactivated vaccine (Fluzone high dose) – age > 65 • Adjuvanted trivalent inactivated vaccine (Fluad) – age > 65 • Quadrivalent inactivated vaccine – produced in cultured cells (Flucelvax) – age > 4 years • Inactivated Influenza vaccine produced using recombinant DNA technology and a baculovirus expression system • Both Trivalent and Quadrivalent formulations (Flubok) • Contains only hemagglutinin antigens • > 18 years old • Standard-dose quadrivalent LAIV • Intranasal • Healthy nonpregnant age 2 – 49 • Produced in eggs • Was not recommended for 2017-2018 season; but now part of ACIP guidelines for 2018-2019 Seasonal Influenza Vaccination

• Vaccine formulations • Choice of vaccine • Healthy nonpregnant adults up to 49 years • Either quadrivalent inactivated or LAIV; ACIP also says trivalent inactivated is also OK • Age > 50 (or if a contraindication for LAIV – immunocompromised, chronic heart or lung conditions, metabolic condition, pregnancy) • Quadrivalent inactivated vaccine • Age 18 – 64 – needle-phobic • LAIV • Trivalent inactivated vaccine (Afluria) with jet injector (PharmaJet Stratis needle free injection system) Seasonal Influenza Vaccination

• Vaccine formulations • Choice of vaccine • Age > 65 • High dose trivalent inactivated vaccine (Fluzone-high dose) – expert opinion (NOT ACIP) • Quadrivalent inactivated vaccine • Trivalent inactivated vaccine • Alternatives Flubok recombinant vaccine or Fluad adjuvant vaccine Seasonal Influenza Vaccination

• Vaccine administration • Ideally before end of October • BUT, give throughout entire flu season • Travel • Year round in the tropics • Summertime outbreaks on cruise ships

• Annual revaccination associated with decreased mortality in adults

• Can give with other vaccines

• Statins • Lower the immune response/antibody titer to hemagglutinin antigens • BUT, Medicare study of 2.8 million beneficiaries • Statin use did not affect visits for ILI or Influenza-related hospitalizations Seasonal Influenza Vaccination

• Vaccine adverse reactions • Soreness at injection site • Arthralgia, myalgia, subjective fever – immune response • Oculorespiratory syndrome – within 24 hours after influenza vaccination • Reported after 2000-01 vaccine • Bilateral conjunctivitis • Facial edema • Cough, wheezing • After change in manufacturing process – substantial drop • GBS – slight increased risk using inactivated flu vaccine during certain flu seasons • Risk substantially less than the overall health risk posed by natural influenza infection • High-dose – more reactions • GI; local • LAIV – rhinorrhea, HA, sore throat