Dermatology Vaccines and More 2016
Dermatologie Vakcíny a Více 2016
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Kenneth J Tomecki, MD
Cleveland Clinic
Cleveland, Ohio  USA
5. Brnĕnsky Dermatologickў
Den Antonina Trўba
Brno, CZ

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5. Brnĕnsky Dermatologickў
       Den Antonina Trўba
•Dermatology Vaccines and More 2016
•Kenneth J. Tomecki MD
Re: Conflicts……
                 nada
NY Cartoon-Disclaimer-1

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Vaccines 2016: A Medical Seatbelt
•Key aspect of medical care
      extremely cost effective
•Primarily Infectious Disease, eg smallpox
•Vaccine preventable diseases
•W/ vaccine neglect 50k+ deaths/ yr

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The Toll of Vaccine Neglect
Source: CDC incl. Death from influenza, pneumococcal dz, hepatitis, etc.  Data ~  2004
The Toll of Vaccine Neglect Consumer Reports November 2001

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Vaccine Rx 2016: Viruses
•Measles/mumps/rubella (MMR)
•Polio (IPV, OPV)
•Hepatitis A, inactivated (Havrix)
•Hepatitis B (plasma) combo, A and B (Twinrix)
•Influenza
•Rotavirus
•Rabies

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Vaccine Rx 2016: Viruses
•Japanese encephalitis
•Yellow fever
•Smallpox (Dryvax)
•Monkeypox
•Varicella (Varivax)
•Herpes zoster (Zostavax)
•Human papillomavirus, HPV (Gardasil, Cervarix)

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Vaccine Rx 2016: Bacteria
•Children and adults
–diphtheria/pertussis/tetanus (DPT)
–pneumococcal pneumonia (pneumococcus)
–H influenza (hib) pneumonia
•Adolescents and adults
–meningococcemia (meningococcus)

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Vaccine Rx 2016: Bacteria
•Adults, but not routinely
–Anthrax
•Adults, but uncommonly
–Lyme disease, vaccine 1998, then w/drawn
–Cholera, 4 vaccines (65-90% effective)
–Typhoid, 2 vaccines,
–
–but not routinely recommended

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Vaccine Rx 2016: Fungi
…..nada
Vaccine Rx 2016: Protozoa
….nada
Vaccine Rx 2016: Parasites
….nada
Vaccine Rx 2016: Cancer
….promising
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Main Derm Vaccines 2016
•Measles / Mumps / Rubella (MMR)
•Varicella vaccine (Varivax, Proquad)
•Herpes Zoster/shingles vaccine (Zostavax)
•HPV vaccines: Cervarix; Gardasil (4/9)
–and.........hepatitis B, leprosy, BCG

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Measles / Mumps / Rubella (MMR)
+Varicella 2005 (Proquad)
•Who / when?
•         Infants 12months+ (12-15 months); 2nd dose 4-6 years
•         Susceptible adults w/o measles immunity
•
•Advantages: obvious
•

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Varicella-Zoster (Varivax, Proquad*)
•Live, attenuated VZV (Oka strain)                  FDA 1995
•Prevents varicella   ↓ severity      ↓ PHN
• ↓ Incidence        ↓ Morbidity/Mortality
•
•Varicella ↓90%          Deaths ↓ 70%
• Immunity now 30 yrs
*Combo vaccine w/MMR -  MMRV
? Protective duration

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•Rx: 12 months - 12 yrs       2 doses (.5ml) SubQ
• 1st Rx @ 12-15 months, 2nd Rx @ 4-6 yrs
•
•Good safety and efficacy
• 97% @ 1st yr, 86% @ 2nd yr
• 81-86% @ 2-8 yrs
•             NB:  112 deaths btw 2002-2007
•
Varicella-Zoster (Varivax, Proquad)
MMWR 4/12/2013

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Herpes Zoster -- ? Best Rx
•Valacyclovir 1g 3x/day for 7 days
–(vs famciclovir or acyclovir),                                                   plus gabapentin
or pregabalin…
• ↓ PHN by 77%

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Zoster (shingles) Vaccine (Zostavax)
Live attenduated VZV (Oka strain)
•Prevention of zoster and PHN
•Rx healthy adults age 50
•Rx: single, subQ dose (.65ml)
•      - higher dose version of VZV vaccine (14x)
•      - ↓ zoster by 50%; ↓ PHN by 65%
•↓efficacy @ 5 years
NEJM 2005;353:2271
FDA approved June 2006

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Zoster Vaccine (Zostavax)
•Safe and effective
•Barriers
– Shortage
– $$/coverage
– +/- MD endorsement
–       …..is it worth it?
–
•? Protective duration        ? Need for booster
–
Ann Intern Med 2006;145:317
Ann Intern Med 2006;145:387

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Herpes Zoster – A New Vaccine
Inactivated Adjuvant Vaccine for Zoster
VZV glycoprotein E and ASO1 adjuvant
•
•HZ/su (recomb inactivated vaccine) GSK
•Phase III: 15k+ pts >50 y/o, 18 countries
•Rx: 2 doses at 2 months
•97% efficacy @ 3 yrs
– ↑ w/adults age 70+
ZOE-50 Study Group
N Engl J Med 2015;372:2087

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HPV Vaccines
•2vHPV (Cervarix) [2], w/ASO4 adjuvant
• x-protective HPV 31, 33, 45
•4vHPV (Gardasil) [1,2]
•9vHPV (Gardasil) [1,2, etc]
• all recombinant L1 capsid    all FDA approved
•
•[1] HPV 6 and 11: 90% venereal warts (condyloma)
•[2] HPV 16 and 18: 70% cervical cancer
hpv_virus_in_women3
Drugs 2010;70:1079
JAMA 2011;205:1424

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•More Recently.....
•
•FDA approves Gardasil 9 for prevention of certain cancers
•caused by five additional types of HPV
•
• HPV 6, 11, 16, 18
• HPV 31, 33, 45, 52, 58 VLPs
• Women: 9-26; men: 9-15
• 3 doses
FDA Dec 10, 2014
CDCP March 27, 2015 / 64(11);300-304
N Engl J Med 2015;372:711-723

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HPV Vaccines
•Rx men and women, ages 9-26
• 3 doses, w/in 6 months
•             2 doses @ 6 months (15 yrs or younger)
• Cervarix - men only
•
•Rx....xx pregnancy; yes for MSM
hpv_virus_in_women3
 Ref: MMWR 2015 March 27;64(11):300

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HPV Vaccines
•Vaccines 95% effective -- warts and neoplasia
•
•Gender-neutral approach to vaccination, but.....
–       +/- acceptance, +/- promotion
–3 doses: 42% girls, 28% boys      (CDC 2015)
–1 dose: 63% girls, 50% boys
–
–                US Goal: 80% by 2020
hpv_virus_in_women3
 Ref: MMWR 2015 March 27;64(11):300

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Hepatitis B Vaccine (Recombivax HB, Engerix-B)
   Combo HAV and HBV (Twinrix)
•Who/when?
•             Pre-exposure prophylaxis, high-risk individuals;
•   hemodialysis pts (ESRD); frequent transfusions;
•   pts w/ diabetes; occupational exposure (medical)
•
•

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Hepatitis B Vaccine (Recombivax HB, Engerix-B)
   Combo HAV and HBV (Twinrix)
•Hepatitis A: 2 doses, 6-18 months apart
•Hepatitis B: 3 doses, over 6 months
• Rx: 3 doses -- 0, 1, 6 months
•
•Protective response: 40-90%
•Duration 20 yrs
•
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Leprosy: Talwar's Vaccine (Immuvac)
•Who/when?
•         Close contact, leprosy pts
•         Folks in endemic areas
•
•Advantages: specific/non-sp immunomodulator
•           ↑ bacterial clearance
•            converts lepromin positive → negative
•
•         ? Duration: 5-7 yrs
•

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BCG (Bacillus Calmette-Guerin)
•Who / when?
–Partially effective in kids: unreliable in adults
–Rx kids and adults at risk
–Rx those w/ occupational risk
–Rx @ birth: ↓ meningitis ↓ miliary TB
–
•
•Advantages: tuberculin conversion
•               ImmunoRx for in situ bladder carcinoma
•

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BCG (Bacillus Calmette-Guerin)
•BCG in the USA
–very selective use
–?health care workers
–?children (neg TB test), w/ continuous exposure
–
•?Leprosy vaccine
•

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Cancer Vaccines
•Sipuleucel-T (provenge)
–Rx metastatic prostate cancer
•GP-100 Peptide Vaccine / IL2
–Rx metastatic melanoma
•Talimogene Laherparepvec (T-Vec)
–Rx metastatic melanoma

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GP-100 Peptide Vaccine and IL-2
•10 yr+ study        pts w/metastatic melanoma
•Rx: vaccine and IL-2 vs IL-2 alone
•     - overall response 16% w/vaccine/IL-2, vs 6% w/IL-2
•       - progression-free survival 2.2 months, vs 1.5 months w/ IL-2
•       - overall survival 17.8 months, vs 11.1 months w/IL-2
• promising, but.......
•
•       risk of arrhythmia w/vaccine/IL-2: 15%
•
N Engl J Med 2011;364:22

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Melanoma: HSV-1 ImmunoRx
   Talimogene Laherparepvec, aka T-Vec (Imlygic, Amgen)
•     Attenuated genetically modified HSV-1, ↑ host response via GM-CSF
•
• Phase 3 Optim trial, 436 pts w/metastatic non-resectable melanoma
• Durable response rate: 16%, vs 2% w/GM-CSF (*IIIB or IIIC)
• Overall response rate: 26%, vs 5%+ w/GM-CSF
• Median survival: 23 months, vs 18 months+ w/GM-CSF
•
•      +/- promising, but.....
•
•
J Clin Oncol May 26, 2015, 3377; Sept 1, 2015, 2812
Intralesional Rx, first oncolytic virus, FDA approved

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? Future Vaccines
•Tuberculosis
–?re-engineered BCG ?prime boost
–?molecular vaccine (several protein antigens)
•Malaria, via RTS, S
•HIV/AIDS
–Sarnoff-Pasteur ‘prime boost’

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BCG / TB  Vaccine
•BCG: ↓ TB meningitis and miliary TB
•Main concern: pulmonary TB
• BCG: no effect
•Now, tuberculosis* and HIV.....
      *latent/healed; 2 billion affected
1.3 million deaths/yr; 9-10 million new cases/yr

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Tuberculosis Vaccine
•15 vaccines ‘in the works’ and 20+ others
• Most live attenuated Mycobacteria                                                or subunit
vaccine proteins, w/ viral vectors
• -- pox viruses (MVA, fowl pox)
• -- adenoviruses (AD5; Ad35)
• -- vesicular stomatitis virus (VSV)
•                           all used as boosters
•
•
•

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Tuberculosis Vaccine
•NB: old M vaccae vaccine for pts w/latent TB and HIV
• 5 intradermal doses (1 yr) HIV pts w/BCG scar
•
•NIH study, 2k pts Dar es Salaam
• 39% efficacy vs TB

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Malaria Vaccine
•RTS, S/ASO1 (RTS, S)
–Recombinant sporozoite protein + hep B surface antigen
•Phase III: 16k kids, 10 centers, 7 countries
• 2 groups: 6-12 wks and 5-17 months
• Rx: 4 doses q monthly x 3, then 18 months
•RTS: 27% efficacy in infants (18% w/ 3 doses)
•RTS: 39% efficacy w/ children
•
•Adv reaction: occas febrile seizures

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And Now……….Mosquirix
•1st ever malaria vaccine
• after 30+ years and $565 million
•?magic bullet…probably not, but.....
•
•225 million new cases/yr
•500k deaths/yr
malaria_special

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Malaria Vaccine
•Definitive vaccine: more antigens (x sporozoite)
–eg liver stage antigens (LSA 1 and 3),
–blood (merozoite) stage antigens* (MSP 1 and 7),
– even gametocytes (Pfs25)
– *RH5 vaccine, ?complement

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Additional Needs...
•Protozoal vaccines
–  eg Leishmaniasis, trypanosomiasis
•Metazoal vaccines
–   eg schistosomiasis, hookworms
•Parasitic vaccines
• ? plasmid-based DNA vaccines
Expert Rev Vaccines 2010;9:175

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HIV/AIDS Vaccine
•Many disappointments
–Envelope protein-based vaccine
–‘prime boost’ approach
–STEP trial (Merck)
–
•Likely solution…T cell-based or antibody-based vaccine
Hiv-Aids

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HIV/AIDS Vaccine
•*Sanofi-Pasteur vaccine
• Heterologous prime boost Rx
• Recombinant canarypox vector vaccine (ALVA C-HIV)
•         w/ booster recombinant glycoprotein 120 (AIDSVAX B/E)
•
•RV144 trial in Thailand, 16k pts
–31% efficacy, but no effect on viral load

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HIV/AIDS Vaccine
•Many other phase I and II trials
–Prime boost approach,
–  w/ neutralizing anti-HIV monoclonal antibodies (PG9, PG18; VRCO)
–HVTN study, w/ multigene, multiclade DNA
    prime recombinant adenovirus 5 (DNA/rAd5)
•
•2 million+ deaths/yr
•2.6 million new cases/yr
•
•

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Vaccines: Current Issues / Hurdles
•Need for more combo vaccines
–Hexavalent vaccine (diphtheria; tetanus; pertussis; H flu type B; polio; hep B)
–Live attenuated MMR-varicella
– ↑ febrile convulsions (2x)
•?transdermal delivery

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Vaccines: Current Issues / Hurdles
•Need for more/better adjuvants
–Toll-like receptors (TLRs)
–Nod-like receptors
–RIG-I-like receptors
–C-type lectin receptors
–Lasers, esp w/if shortages
           eg ablative fraction laser (AFL)

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Current Vaccine Adjuvants
•5 licensed adjuvants..
–MF59 (Novartis)
–AS03 and AS04 (GSK)
–Liposomes (Crucell)
–AF03 (Sanofi-Pasteur)

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Vaccines: Non-scientific Issues / Hurdles
•Benefit vs fear / hesitation
•Discomfort i.e. needle sticks
•Inconvenience; cost
•? Side effects
•Myths
•Anti-vaccination movement
•? Need for vaccination
•? Dangers of vaccination
Vaccine 2003;21:593

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Vaccines: ‘Not Just for Kids’
•Vaccines  -  safe and effective
–Usually only minor side effects
–
•True contraindications are rare
• i.e. hypersensitivity reactions, neurologic complications
•
•50k+ deaths each year (USA)
• Most flu-related, 95% adults 60+
flu-shot

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Vaccination in General……yes
•Avoid w/ true contraindications
•Postpone w/ moderate - severe febrile illness
•Ok to proceed
– - Current or recent mild illness, with or w/o fever, including diarrhea
– - Current or recent antibiotic Rx, except oral typhoid (Ty21a) vaccine
– - Previous mild/moderate rxn after vaccination
– - Personal h/o allergies
– - FH/o adv rxns to immunizations
–

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Vaccine Recommendations CDC, adults 50+
•Influenza
•Pneumococcal
•Td/dap*
•MMR**
•Zoster
•Hepatitis A
•Hepatitis B
•Meningitis
* tetanus/diphtheria/pertussis
** measles/mumps/rubella

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Influenza Vaccine
•Rx: age 50+, annually (3 strains)
•not nasal spray
•33% adults (1989), 70% (2003)
40% young adults at risk
MMWR 2012; 61:66

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Pneumococcal Vaccine
•15% adults (1989), 64% (2003)
• 18% young adults at risk
•
MMWR 2012; 61:66
•Rx: age 65+; 50+, if risk factors                                  heart/lung disease,
diabetes,                                    lymphoma, leukemia, asthma,
        healthy adults in health care settings

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MMR Vaccine
•Rx: adults age 50+, if unsure about status
(most exposed or vaccinated)
? check serology, but....
• efficacy before pregnancy
Td/dap* Vaccine
•Rx: adults age 50-64 (booster)
•Td booster, age 65+
•  efficacy during pregnancy
•
•
* Tetanus / diphtheria / pertussis

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Tetanus/Diphtheria Immunity
Tetanus
•Overall 30.3% susceptible
•>70 years 72.2% susceptible
Diphtheria
•Overall 37.6% susceptible
•50-59 years 52.8% susceptible
47% adults w/protective Abs; 91%  children

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Meningitis Vaccine
•Rx: adults age 50+, if never vaccinated or if at risk
•For adults < age 55 w/o vaccination:                                                    conjugate
vaccine (lifelong immunity)
•For adults > age 55: polysaccharide vaccine (3-5 yrs immunity)
•
CDC: Rx adults, ages 16-23, 3 doses serogroup B (MenB)




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Routine Vaccines for Travel
•Inactivated
•Hepatitis A*
•Tdap
•Poliomyelitis
•Influenza
•Pneumococcal
•Live-attenuated
•MMR
•Varicella
* OK even the day before leaving on the trip

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Travel Specific Vaccines
Inactivated
•Meningococcal *
•Typhoid (Vi antigen)
•Hepatitis A �
•Hepatitis B �
•Japanese encephalitis
•Rabies
Live-attenuated
•Yellow fever
•Typhoid (Ty21a oral)
† TwinRix combined HepA and HepB vaccine
*  New conjugate meningococcal vaccine

> Slide124



“Další injekce proti chřipce, Jozef.”



brno7a
Děkuji
Snoopy alone




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Top 10 US Public Health Advances
•Vaccination
•Motor vehicle safety
•Safer workplaces
•Control of infectious diseases
•↓ death from coronary heart disease and stroke
•Safer, healthier food
•Healthier mothers and babies
•Family planning
•Fluoridation of drinking water
•Recognition of tobacco as a health hazard
CDC  MMWR  1999;43:241
cdc_logo

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Vaccine Impact: Morbidity / Mortality
Roush SW et al. JAMA 2007; 298:2155
D
P
T
IPV
Smallpox
M
R
M
Varicella
HAV
HBV
Hib
Pn

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Adverse Effects of Vaccines
    Evidence and Causality
•Varicella zoster
•Influenza
•Hepatitis A
•Hepatitis B
•
•Tetanus
•Meningococcal
•MMR
•HPV
Institute of Medicine August 2011

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Evidence Supports Causal Relationship
•Varicella zoster:
– disseminated varicella with or w/o infection                                     vaccine viral
replication with or w/o infection
•MMR: febrile seizures and                                                      measles inclusion
body encephalitis
•6 vaccines: anaphylaxis                                                                    (MMR,
varicella zoster, influenza,                                       hepatitis B, meningococcal,
tetanus)
•Injection vaccine: syncope and                                                deltoid bursitis
(frozen shoulder)

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+/- Causal Relationship
•HPV and anaphylaxis
•MMR and transient arthralgia
–women; children
•Trivalent flu vaccine (Canada)
–oculo-respiratory syndrome

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No Causal Relationship
•MMR and autism
•MMR and type 1 diabetes
•DTaP (tetanus) and type 1 diabetes
•Inactivated influenza and Bell's palsy
•Inactivated influenza and asthma exacerbation
•Inactivated influenza and reactive airway disease

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Vaccines: Adverse Event Reporting
•Anaphylaxis, w/in 7 days
•Encephalopathy/encephalitis, or seizures
•Any sequelae, other serious/unusual event

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Vaccine Specific Reportable Events
•Tetanus: brachial neuritis w/in 28 days
•Pertussis: encephalopathy/encephalitis w/in 7 days
•Measles/mumps/rubella: encephalopathy/encephalitis w/in 15 days
•Rubella: chronic arthritis w/in 6 weeks
•Measles: TTP w/in 7-30 days
•Oral polio: paralytic polio w/in 30 days - 6 months (not in use USA)

69



> Slide153
“Kde je pivo vaří,
tam je to dobré”
- old Czech saying