New Vaccines

Pagakrong LumbiganonPope Kosalaraksa

Department of Pediatrics,Faculty of Medicine,Khon Kaen University

•History of Vaccination•New:Vaccines in process of development•New vaccine: Rotavirus vaccine

Influenzae vaccine•New use: Zoster vaccine

Pertussis vaccine for adult

Smallpoxvariola virusgreatest killerkill 10%-20% population1/3 all deaths in children

Variolation

Edward Jenner1749-1823a surgeon

1796: James Phippspus from cowpox hand of milkmaid Sarah Nelmes

Father of Immunology

Development of human vaccines18th century 1798 Smallpox: Live-attenuatedcowpox (Latin: vacca = a cow)

‘ Vaccination ’1980 WHO Assembly declared‘the world and its peoples’ free fromendemic smallpox

18th century1798 Smallpox

19th century1885 Rabies : Live-attenuated1896 Typhoid,

Cholera : Killed whole organism1897 Plague

20th century1927 Tuberculosis BCG : Live attenuated1935 Yellow fever1926 Pertussis : killed whole organism1936 Influenza1938 Rickettsia (typhus)1923 Diphtheria : Protein or polysaccharide1927 Tetanus

After World War II :•live-attenuated vaccine•polio (oral) varicella•measles rotavirus (reassortants)•mumps rubella cold-adapted influenza(CAIV)•adenovirus typhoid salmonella Ty21a

•Killed whole organism•Protein or polysaccharide•Genetically engineered

Killed whole organism Protein or polysaccharidepolio (injected) pneumococcusrabies( cell culture) meningococcusJapanese encephalitis Haemophilus influenzae PRPtick-borne encephalitis pneumococcal conjugatehepatitis A Meningococcal conjugatecholera H. influenzae PRPP-conjugate

hepatitis B (plasma derived)typhoid (Vi)acellular pertussis, anthrax

Genetically engineered

• hepatitis B recombinant (yeast or mammalian cell derived)

• acellular pertussis (some component)

Vaccine development• discovery, process engineering • toxicology, animal study• Human studyPhase I safetyPhase II target population safety, immunogenicityPhase III large target population efficacy

New vaccines :Research and development statusInitiative for Vaccine Research (IVR)WHO, April 2005•SARS: whole inactivated v; Sinovac China :Phase I•TB: BCG : efficacy <20% - >80%

live, recombinant MVA-Ag85A :Phase I completedwww.who.int/vaccine_research/en/

•HPV: human papilloma virus vaccine•cervical cancer•HPV 6,11,16,18 L1protein VLPs yeast 3 doses Phase III completed; licensure pendingMerck 4 types 16,18, 6,11 , GSK 2 types 16,18limitations

• type 16,18 cause 70% of CA cervix, another 30% ?• duration of immunity: unknown ?• high risk for infection age 18-25, target pre-adolescent ?www.who.int/vaccine_research/en/

• Cholera : killedO1 and O139 whole cell Vietnam Phase II

• Shigellosis : live attenuated S. flexneri/sonneioral China, Phase III

• HIV/AIDS : live,recombinant ALVAC-env/gag/pol/nef+recombinant cladeSanofi-Pasteur/VaxGen/Min of Health of Thailand Phase III (drug user) , etc…….

Rotavirus vaccine Influenza vaccine

Varicella vaccine Zoster vaccine

Aerosol or direct contactinoculation of respiratory mucosa

v. replication in regional LNinfected cells into capillaries

primary viremia> replication in liver/spleen, other RE sites

Secondary viremia:mononuclear cells transport v. to skin and mucous mem.V. release into respiratory secretions

replication in epidermal cellsv. transported to dorsal root ganglia latency establishedVZV-specific immunity cessation of v. replicationArvin A. Virology, 1995

Varicella in children: mild illnesscomplication:• secondary bacterial infections• encephalitis, cerebellar ataxia 2-6 days after rash• elevation of AST, acute thrombocytopenia• nephritis, arthritisAdults: greater morbidity and mortality• varicella pneumonia : 1-6 days after onset of rash

Live-attenuated varicella vaccine1974 Michiaki Takahashi (Biken) “ Oka strain”1984 some European countries

licensed for use in high risk children1987 Japan1988 Korea1989 Japan and Korea for healthy children1995 USA, Sweden, Germany1998 Canada1997 available in Thailand

Varicella vaccine : Immunogenicitychildren 12 mo-12y 1 dose > 95% humoral and cell-mediated immunity> 13y 1 dose 78% , 2 dose 99%

Effectivenesspreventing moderate to severe varicella > 95%mild infection 70-85%

Duration of immunitystudy in USA protection for at least 14 yJapan at least 25 y

FAQs, NIP, CDC 2005

Adverse events: mild20% injection site reaction3-5% localized rash, 3-5% gen. Varicella rash

Recommedation : USAchildren > 12 months -12 y 1 dose SC> 13 y - adult 2 doses 4-8 weeks apart

Red Book 2003

Thailand optional or PDIST recommendation:> 10 y who is susceptible to varicella

• Increase in herpes zoster after widespread use of varicella vaccine?

Herpes zoster Children<10 y = 74/100,000 person/yElderly 80-89 y = 1010/100,00 person/y

Ragozzino MW. Medicine 1982;61:310-6

Herpes zoster Complication:• post herpetic neuralgia rare before age 50

increase with advancing age after age 60 y = 50%after age 75 y = 75%

• facial palsy, dendritic keratitis, oral lesions,• neurogenic bladder dysfunction, etc

Ragozzino MW. Medicine 1982;61:310-6Nurmikko T. Neurology 1995;45(suppl8:S54-5

Age-related decline in VZV-specific cell-mediated immunityBurke BL. Arch Intern Med 1982;142:291-3

•Increase rates and severity of zoster in elderly associated with decrease cell -mediated immunity•as also in malignancy, HIV infection•due to loss of cell -mediated immunity to VZVLevin MJ. Infect Dis Clin North Am1996;10:657-76

• Reexposure to VZV circulate in a community enhances VZV specific immunity (exogenousboosting) , reduces the risk of reactivation,decrease risk herpes zosterHope-Simpson. Proc R Soc Med 1965;58:9-12Brisson M. Vaccine 2002:20; 2500-7.

• Herpes zoster : adults living with children incidence ratio = 0.75 (95%CI 0.63-0.89)Brisson M. Vaccine 2002:20; 2500-7.

Pathogenesis of herpes zoster modified from Hope-Simpson RE. 1965

• Lack of reexposure to circulating virus +decline of cell-mediated immunity to VZV in elderly

• Mathematical model:with 90% vaccination rate in children

a 30% increase in H. zoster

Brisson M. Epidemiol Infect 2000;125:651-9

Immune response of the elderly to live-attenuated varicella vaccine

• 202 VZV-immune adults age > 55 to > 80 y Var vac enhancement of VZV-specific cellular immunity persist to at least 4 y---frequency of PBMC response to VZV antigen ---IFN gamma production in VZV stim. PBMC

cultures• 10-15% not response

Levin MJ. J Infect Dis 1992;166:253-9, 1994;170:P522-6

Varicella vaccination in Elderly• Local reactions < 25%• Systemic reactions

fever <1%, headache 4%myalgia and rash < 3%sore throat , cough, nausea <3% each

• Possible systemic spread of vaccine virus 6/245 injection, all were mild skin rashes

Levin MJ. J Infect Dis 1992;166:253-9, 1994;170:P522-6

Trannoy E. Vaccine 2000;18:1700-6• RCT double-blind n= 200 age 55-75 yr • Dose response study

Oka vaccine 3,200, 8,500, 41,650 pfu VS pneumococcal vacresult: CMI response, no relationship between dose and response

Levin MJ. J Infect Dis 2003;188:1336-44• n=196 age > 60 yr previous VZV vaccination > 5 yr• booster vaccine high potency 50,000 pfu/dose of att vaccine

result: safe , immunogenic

Zoster vaccine• Randomized, double-blind, placebo-controlled

trial • subjects 38,546 > 60 yrs median 69 yrs( 6.6%, 6.9% of vaccine, placebo gr age > 80 y)Nov 1998- Sep 2001, follow up till April,2004• ‘shingles’ vaccine = 10x quantity of VZV

to prevent chickenpox

Oxman MN, et al. N Engl J Med 2005;352:2271-84

Effect of Zoster vaccine•median 3.12 y of surveillance for herpes zoster

Vaccine Placebo•comfirmed case of HZ 315/19,254 642/19,247•PHN 27 80• reduced burden of illness 61.1%• reduced postherpetic neuralgia 66.5%• reduced incidence of herpes zoster 51.3%

Oxman MN, et al. N Engl J Med 2005;352:2271-84

Complications•pneumonia•seizure•encephalopathy(22%,2%, 0.5%infant<12 months)

Pertussis vaccine: whole cell, acellular

Pertussis

Pertussis vaccine whole cell wP DwPT reaction•fever 1/2•persistent crying >3h 1/100•fever >40.5 0C 1/330•hypotonic-hyporesponsive episodes 1/1750•seizure within 48 h 1/1750•encephalopathy 0-1/1,000,000MMWR1996;45(RR-12):1-35

acellular pertussis vaccine aP•PT pertussis toxoid•FHA filamentous hemagglutinin•PRN pertactin (outer membrane 69-kd protein)•FIM 2+3 fimbrial protiens (agglutinogens)Both for children < 7 years Contraindications: anaphylaxis

encephalopathy

Reported pertussis5.4/100,000 (1984) 34.7/100/000 (1994)in adolescents&adults (Canada)USA (MMWR 2004;53:687)

•waning vaccine-induced immunity•availability of serology as Dx method•improved reporting, greater awareness

Pertussis is a frequent cause of prolonged cough illness in adults and adolescents• Age > 12 yrs cough of 1-8 weeks’ duration• Lab confirmed pertussis (C/S,PCR,serology)

88/442 prevalence 19.9% (95%CI 16.3-24.0)mean age (range) 38.3 (12.3 - 87.7)Senzilet LD Clin Infect Dis 2001;32:1691-7

• source of transmission to infants and children

• Infants < 6 months high risk for severe pertussismore serious complicationMMWR2002;51:73-6

• Infant pertussis: who was the source?264 case-infants 32% mothers

43% another family member

Bisgard KM. Pediatr Infect Dis 2004;23:985-9

• New pertussis vaccination strategies beyond infancyForsyth KD Clin Infect Dis 2004;39:1802-9

• Pertussis vaccination beyond childhoodSerres GD Lancet 2005;365:1015-6

• Acellular pertussis vaccine for adolescentscomponent ap = 1/3-1/4 dilution of pediatric formulation (Ap)Pichichero ME Pediatr Infect Dis J 2005;24:S117-26

Randomized, double-blind,comparative trialCombined td & 5 component pertussis vaccine for use in adolescents and adults• Aug 2001-Aug 2002, 39 US clinical centers

age 11-64 y 0.5 ml Tdap Td11-17 527 51618-64 743 510

Pichichero ME JAMA 2005;293:3003-11

Antibody >0.1IU/ml for D, T in 94%, 100%P: Antibody to pertussis toxoid, PT

filamentous hemagglutinin ,FHA pertactin, PNfimbriae types 2 ,3 FIM2,3

> in infant 3 dose at 2,4,6 months 2.1-5.4 folds

Pichichero ME JAMA 2005;293:3003-11

Q & A

Concerns•Herpes zoster in vaccinee after varicella vaccination

study in children with leukemia :zoster following immunization 2%15% with past natural infection

Hardy IB. N Engl J Med 1991;325:1545-50

•less possibility of latency in ganglia from vaccine virusthan wild-type VZVGershon AA. J Infect Dis 1992;166(suppl):S63-8

•vaccine virus reactivation : Yesbut less common than wild-type VZV

•vaccine virus is inhibited by acyclovir

Question 1: Long term vaccine effectiveness• case-control study : 3/1997-6/2003 , Connecticut• 339 cases Dx by PCR : 669 control• vaccine effectiveness : protection up to 8 y• 1st y = 97% (95%CI= 91-99%)• y 2-8 = 84% (95%CI= 76-89%), p=.003( During study:VZV still circulate in the community

immunity boosted by subclinical infection)Vazquez M. JAMA 2004;291:851-5

• Outbreaks despite high rate of immunization vaccine efficacy = 44%

Galil K. N Engl J Med 2002;347:1909-15• Chickenpox outbreak in a highly vaccinated

school populationstudents vac >5y 15/65 (23%): vac<5y 3/87 (3%)= 6.7x (95%CI: 2.2-22.9) as likely to develop breakthrough disease

Tugwell BD. Pediatrics 2004;113:455-9

• If interval between vaccination and exposure is significantly associated with breakthrough disease

• Routine booster vaccination for children ?• Need further study

Kuter B. Pediatr Infect Dis J 2004;23:132-7Vazquez M. Pediatr Infect Dis J 2004;23;871-2Tugwell BD. Pediatrics 2004;113:455-9

Question 2 : Age at vaccination • case-control study :339 cases Dx by PCR:669 control• effectiveness : in the first year after vaccination

vaccinated at <15 months =73%vaccinated at >15 months = 99%

Vazquez M. JAMA 2004;291:851-5

• Younger age at vaccination may increase risk of vaccine failure Galil K. J Infect Dis 2002186:102-5