Prevention of Hepatitis A Prevention of Hepatitis A during outbreaks during outbreaks and post-exposureand post-exposure

Paolo BonanniPaolo Bonanni

Department of Public HealthDepartment of Public HealthUniversity of Florence, ItalyUniversity of Florence, Italy

Hepatitis A: epidemiological patternsHepatitis A: epidemiological patterns

EndemicityEndemicitylevellevel

Age of infectedAge of infectedsubjectssubjects

OutbreaksOutbreaks

HighHigh

IntermediateIntermediate

LowLow

< 5 years< 5 years

5-15 years 5-15 years

> 20 years> 20 years

RareRare

Common: community-wide; Common: community-wide; food-borne (shellfish); water-food-borne (shellfish); water-borne; close personal contactborne; close personal contact

Occasional: day-care Occasional: day-care centers;centers;food-borne (shellfish);food-borne (shellfish);water-borne;community-water-borne;community-wide; close personal contactwide; close personal contact

Source: WHO, 1995 (modified)Source: WHO, 1995 (modified)

Risk groupsRisk groupsfor clinical diseasefor clinical disease

ChildrenChildren

ManyMany

Contacts of Contacts of cases; cases;

travellers; travellers; drug users; drug users;

homosexualshomosexuals

Age (years)

Ser

op

reva

len

ce o

f an

ti-H

AV

(%

)

Improvement in hygiene

Epidemiological shift in Epidemiological shift in seroprevalence of anti-HAVseroprevalence of anti-HAV

0

20

40

60

80

100

10 20 30 40 50

(from Van Damme P, 1994)(from Van Damme P, 1994)

Epidemiological changes of Epidemiological changes of hepatitis A infectionhepatitis A infection

• Consequence of improved hygiene and sanitation, Consequence of improved hygiene and sanitation, better socio-economic situation, changes in family better socio-economic situation, changes in family sizesize

• Reduced circulation of HAV at young age and Reduced circulation of HAV at young age and growing number of susceptibles in younger age growing number of susceptibles in younger age groups and adultsgroups and adults

• End result is a higher possibility for outbreaks to End result is a higher possibility for outbreaks to occur and a more severe disease since infection is occur and a more severe disease since infection is often acquired by adolescents and adultsoften acquired by adolescents and adults

Outbreak of hepatitis A in a canteen in Outbreak of hepatitis A in a canteen in Genoa (Italy), 1993 Genoa (Italy), 1993

Epidemiological investigationEpidemiological investigation

Total no. of anti-HAV negative employees = 468 Total no. of anti-HAV negative employees = 468 (37% of all workers)(37% of all workers)

Attack rate = 11.1%Attack rate = 11.1%

Total no. of cases = 56Total no. of cases = 56

Primary cases = 52Primary cases = 52

Secondary cases = 4Secondary cases = 4

Asymptomatic = 1Asymptomatic = 1

Symptomatic = 51Symptomatic = 51

(Bonanni P et al., Abstracts IX Triennial International Symposium(Bonanni P et al., Abstracts IX Triennial International Symposium on Viral Hepatitis. April 21-25, 1996, Rome, Italy, pp. 65) on Viral Hepatitis. April 21-25, 1996, Rome, Italy, pp. 65)

Why is this old disease of growing Why is this old disease of growing importance?importance?

The exposure is changing due to:The exposure is changing due to:– dining out culturedining out culture– preference for exotic food, fast food, etc.preference for exotic food, fast food, etc.– growing trend to send young children to day growing trend to send young children to day

care (at an earlier age)care (at an earlier age)

if we are not travelling to hepatitis A, if we are not travelling to hepatitis A, hepatitis A is travelling to us!hepatitis A is travelling to us! Changing migration patternsChanging migration patterns increasing number of people on the moveincreasing number of people on the move

Importation of hepatitis AImportation of hepatitis A

• Foreign born mobile populations and the children Foreign born mobile populations and the children born to first generation migrants are an increasing born to first generation migrants are an increasing population cohort in many European countries, population cohort in many European countries, including Italyincluding Italy

• Immigrants residing in these countries visit Immigrants residing in these countries visit annually their country of birthannually their country of birth

• their children born in low endemic countries their children born in low endemic countries contract HAV on holiday in parents’ countrycontract HAV on holiday in parents’ country

• these children cause secondary infections upon these children cause secondary infections upon their returntheir return

General measures for hepatitis A General measures for hepatitis A preventionprevention

• In household settings:In household settings:– good personal hygiene (hand washing practices)good personal hygiene (hand washing practices)– attention to proper food preparationattention to proper food preparation

• At the community levelAt the community level– provision of safe drinking waterprovision of safe drinking water– proper disposal of sanitary waste proper disposal of sanitary waste – good hand washing practices among food handlers and good food-good hand washing practices among food handlers and good food-

handling techniqueshandling techniques– surveillance of water beds for shellfishsurveillance of water beds for shellfish– control of the commercial distribution of shellfish from unsupervised control of the commercial distribution of shellfish from unsupervised

areasareas

Impact of general prophylaxis Impact of general prophylaxis measures on HAV epidemiologymeasures on HAV epidemiology

Fundamental to reduce the overall Fundamental to reduce the overall circulation of the virus, circulation of the virus, butbut often unable often unable to put outbreaks under control, especially to put outbreaks under control, especially in situation of high promiscuity and in situation of high promiscuity and common use of toilet facilities by many common use of toilet facilities by many people (e.g. day care centres and closed people (e.g. day care centres and closed communities)communities)

Use of standard immune globulin Use of standard immune globulin during hepatitis A outbreaksduring hepatitis A outbreaks

Demonstration of about 85% efficacy in post-exposure Demonstration of about 85% efficacy in post-exposure prophylaxis when given within 14 days after exposure prophylaxis when given within 14 days after exposure (Mosley JW et al., (Mosley JW et al., Am J EpidemiolAm J Epidemiol 1968; 87: 539-550) 1968; 87: 539-550), , but:but:• IgIg was often unable to stop community-wide outbreaks, was often unable to stop community-wide outbreaks, probably due to the limited time of protection compared probably due to the limited time of protection compared to the usual to the usual lenght lenght of epidemicsof epidemics• IgIg is often difficult to obtain in stocks for use in the is often difficult to obtain in stocks for use in the populationpopulation• IgIg are not well accepted because they are obtained from are not well accepted because they are obtained from human bloodhuman blood• the concentration of anti-HAV in the concentration of anti-HAV in IgIg has declined in the has declined in the last decades as a consequence of decreased viral last decades as a consequence of decreased viral circulationcirculation

Effectiveness of human immune globulin Effectiveness of human immune globulin or vaccine in controlling outbreaks of or vaccine in controlling outbreaks of

hepatitis Ahepatitis A

Depends on:Depends on:

• how well the community at risk is defined how well the community at risk is defined

• how high is the coverage achieved with the how high is the coverage achieved with the interventionintervention

• the efficacy of the intervention at the the efficacy of the intervention at the individual levelindividual level

• the phase of the outbreak when the the phase of the outbreak when the intervention is implementedintervention is implemented

Impact of hepatitis A vaccine during Impact of hepatitis A vaccine during outbreaksoutbreaks

1) 1) Public health perspective:Public health perspective: ability of the ability of the intervention to shorten the duration of the intervention to shorten the duration of the outbreak, although cases may still occur in outbreak, although cases may still occur in vaccineesvaccinees

2) 2) Individual perspective:Individual perspective: ability of vaccination ability of vaccination to avoid secondary infections in contacts of to avoid secondary infections in contacts of casescases

Experience of hepatitis A vaccination Experience of hepatitis A vaccination during an outbreak in a nursery school during an outbreak in a nursery school

of Tuscany, Italyof Tuscany, Italy- background -- background -

• Start of the outbreak in late October, 1996 in a nursery Start of the outbreak in late October, 1996 in a nursery school located in a village of Tuscany, local health school located in a village of Tuscany, local health district n. 11 (total population about 80,000 subjects) district n. 11 (total population about 80,000 subjects)

• Yearly incidence of hepatitis A in the area 1985-1995: Yearly incidence of hepatitis A in the area 1985-1995: 2.5/100,000 population2.5/100,000 population

• 41 children attended the nursery school41 children attended the nursery school

• Index case: child returning from AlbaniaIndex case: child returning from Albania

• Confirmation of cases by detection of IgM anti-HAVConfirmation of cases by detection of IgM anti-HAV

(Bonanni P. (Bonanni P. et al.,et al., Epidemiology and InfectionEpidemiology and Infection 1998; 121: 377–380) 1998; 121: 377–380)

Experience of hepatitis A vaccination during Experience of hepatitis A vaccination during an outbreak in a nursery school an outbreak in a nursery school

of Tuscany, Italyof Tuscany, Italy- results -- results -

• 11 cases (5 in children and 6 in household contacts) 11 cases (5 in children and 6 in household contacts) detected by December 6, 1996detected by December 6, 1996

• Start of an immunisation programme without use of Start of an immunisation programme without use of immunoglobulin on December 7, 1996immunoglobulin on December 7, 1996

• 33 schoolchildren (2 parents’ refusals), 11/36 33 schoolchildren (2 parents’ refusals), 11/36 cohabitant children, all 6 adult school-workers and cohabitant children, all 6 adult school-workers and 10/78 adult household contacts were vaccinated10/78 adult household contacts were vaccinated

• 2 vaccinated schoolchildren developed hepatitis A 2 vaccinated schoolchildren developed hepatitis A 5 and 7 days after immunisation, respectively5 and 7 days after immunisation, respectively

• 3 children vaccinated with unspecific gastroenetritis 3 children vaccinated with unspecific gastroenetritis turned to clear hepatitis A within few days turned to clear hepatitis A within few days

(Bonanni P. (Bonanni P. et al.,et al., Epidemiology and InfectionEpidemiology and Infection 1998; 121: 377–380) 1998; 121: 377–380)

Experience of hepatitis A vaccination during Experience of hepatitis A vaccination during an outbreak in a nursery school an outbreak in a nursery school

of Tuscany, Italyof Tuscany, Italy- results and discussion -- results and discussion -

• 2 cases of hepatitis A occurred among cohabitant immunised 2 cases of hepatitis A occurred among cohabitant immunised children 7-10 days after a single dose of vaccine, respectivelychildren 7-10 days after a single dose of vaccine, respectively

• All other children completed the vaccination courseAll other children completed the vaccination course• Last case of hepatitis A detected on February 7, 1997Last case of hepatitis A detected on February 7, 1997• Overall number of cases detected: 11 in schoolchildren Overall number of cases detected: 11 in schoolchildren

(attack rate = 26.8%) and 10 in their household contacts (attack rate = 26.8%) and 10 in their household contacts (attack rate on all cohabitants, irrespective of susceptibility: (attack rate on all cohabitants, irrespective of susceptibility: = 9%)= 9%)

• Two cases occurred in grandmothers of schoolchildrenTwo cases occurred in grandmothers of schoolchildren• Role of vaccination in the extinction of the outbreak highly Role of vaccination in the extinction of the outbreak highly

likelylikely

(Bonanni P. (Bonanni P. et al.,et al., Epidemiology and InfectionEpidemiology and Infection 1998; 121: 377–380) 1998; 121: 377–380)

Large-scale hepatitis A vaccination during an Large-scale hepatitis A vaccination during an outbreak in Genoa, 1997 (1)outbreak in Genoa, 1997 (1)

• First case of hepatitis A detected in an immigrant child First case of hepatitis A detected in an immigrant child returning from a travel to his original countryreturning from a travel to his original country

• Another case occurred two weeks later in a child attending Another case occurred two weeks later in a child attending the same nursery school of the index casethe same nursery school of the index case

• Vaccination programme started immediately, involving Vaccination programme started immediately, involving 26/29 children attending the school26/29 children attending the school

• Two further cases occurred within 3 weeks in contacts of Two further cases occurred within 3 weeks in contacts of previous cases who attended two other schoolsprevious cases who attended two other schools

Bruzzone B.M., Abstracts of the 7th National Congress of Travel and Migration Medicine, 1999Bruzzone B.M., Abstracts of the 7th National Congress of Travel and Migration Medicine, 1999

Large-scale hepatitis A vaccination during an Large-scale hepatitis A vaccination during an outbreak in Genoa, 1997 (2)outbreak in Genoa, 1997 (2)

• Vaccination was extended to children of 17 nursery schools of the Vaccination was extended to children of 17 nursery schools of the historical centre of the city (1453/2033 - 71% subjects -were historical centre of the city (1453/2033 - 71% subjects -were immunized) and offered to susceptible family members, teachers and immunized) and offered to susceptible family members, teachers and school operatorsschool operators

• Eight further casesEight further cases occurred after vaccination: 5 in the first school occurred after vaccination: 5 in the first school involved (3 in immunised children within 12 days, and 2 in non-involved (3 in immunised children within 12 days, and 2 in non-vaccinated subjects) and 3 in the second school involved (2 in vaccinated subjects) and 3 in the second school involved (2 in vaccinees within 2 days and 1 non immunised)vaccinees within 2 days and 1 non immunised)

• One year later a new imported case occurred in one of the school One year later a new imported case occurred in one of the school involved in the vaccination programme: involved in the vaccination programme: no further casesno further cases, in spite of , in spite of several contacts several contacts

Bruzzone B.M., Abstracts of the 7th National Congress of Travel and Migration Medicine, 1999Bruzzone B.M., Abstracts of the 7th National Congress of Travel and Migration Medicine, 1999

• Hepatitis A vaccine was used in susceptible family contacts Hepatitis A vaccine was used in susceptible family contacts (age 1-40 years) of acute hepatitis A cases in a trial (age 1-40 years) of acute hepatitis A cases in a trial performed in Naples in 1997performed in Naples in 1997

• Index cases were defined as IgM anti-HAV+ subjects with Index cases were defined as IgM anti-HAV+ subjects with primary infection, ALT ≥ twice the upper normal value and primary infection, ALT ≥ twice the upper normal value and hospitalised within 1 week of onset of symptomshospitalised within 1 week of onset of symptoms

• Household contacts participating in the study were Household contacts participating in the study were randomly assigned to treatment (1 dose of HA vaccine) or randomly assigned to treatment (1 dose of HA vaccine) or to no treatment according to the week of enrolmentto no treatment according to the week of enrolment

• Their blood was drawn at time of enrolment and at day 14 Their blood was drawn at time of enrolment and at day 14 and 45 of follow-up. IgM anti-HAV positive subjects at day and 45 of follow-up. IgM anti-HAV positive subjects at day 0 and 14 were classified as co-primary cases 0 and 14 were classified as co-primary cases

Efficacy of hepatitis A vaccine in prevention of Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised secondary hepatitis A infection: a randomised

trialtrial- background -- background -

(Sagliocca et al., (Sagliocca et al., Lancet 1999Lancet 1999; 353: 1136-1139); 353: 1136-1139)

• Out of 356 eligible cases, 146 agreed to participateOut of 356 eligible cases, 146 agreed to participate

• 351 their household contacts underwent blood tests351 their household contacts underwent blood tests

• All those assigned to the treatment group received a vaccine All those assigned to the treatment group received a vaccine dose within 8 days from onset of symptoms in index cases dose within 8 days from onset of symptoms in index cases (56% within 4 days)(56% within 4 days)

• 132 contacts (37.6%) were already immune, and 9 were co-132 contacts (37.6%) were already immune, and 9 were co-primary casesprimary cases

• Hepatitis A vaccine showed a Hepatitis A vaccine showed a 79% 79% protective efficacy protective efficacy (95% (95% c.i.: 7-95%) c.i.: 7-95%) in the prevention of secondary hepatitis A when in the prevention of secondary hepatitis A when households were consideredhouseholds were considered

• Efficacy was Efficacy was 82%82% (95% c.i.: 20-96%)(95% c.i.: 20-96%) when household when household contacts were analysed as independent participantscontacts were analysed as independent participants

Efficacy of hepatitis A vaccine in prevention of Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised secondary hepatitis A infection: a randomised

trialtrial- results -- results -

(Sagliocca et al., (Sagliocca et al., Lancet 1999Lancet 1999; 353: 1136-1139); 353: 1136-1139)

• Vaccination was required in 18 participants to prevent one Vaccination was required in 18 participants to prevent one secondary infection (the number may vary according to secondary infection (the number may vary according to number of immune subjects)number of immune subjects)

• The study was stopped before reaching the foreseen sample The study was stopped before reaching the foreseen sample size (160 households in the two arms) because of ethical size (160 households in the two arms) because of ethical considerations (demonstration of efficacy)considerations (demonstration of efficacy)

• The rate of non-participation to the study was higher in less The rate of non-participation to the study was higher in less educated subjects, but this probably did not affect efficacyeducated subjects, but this probably did not affect efficacy

• Efficacy may be underestimated (non-continuos exposure of Efficacy may be underestimated (non-continuos exposure of contacts due to hospitalisation of cases within 1 week of contacts due to hospitalisation of cases within 1 week of disease onset)disease onset)

Efficacy of hepatitis A vaccine in prevention of Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised secondary hepatitis A infection: a randomised

trialtrial- considerations -- considerations -

(Sagliocca et al., (Sagliocca et al., Lancet 1999Lancet 1999; 353: 1136-1139); 353: 1136-1139)

Problems and opportunities of use for hepatitis A Problems and opportunities of use for hepatitis A vaccine during outbreaks and post-exposure (1)vaccine during outbreaks and post-exposure (1)

ProblemsProblems

• No direct comparison between vaccine and immune globulin during No direct comparison between vaccine and immune globulin during outbreaks or for the prevention of secondary cases has been outbreaks or for the prevention of secondary cases has been performed (it would require a large number of subjects). performed (it would require a large number of subjects). Experimental studies of vaccine efficacy during outbreaks are not Experimental studies of vaccine efficacy during outbreaks are not available and would imply ethical problems should a no-treatment available and would imply ethical problems should a no-treatment group be includedgroup be included

• Since the data from the only clinical trial reported in the literature Since the data from the only clinical trial reported in the literature regarded early identified contacts of cases, prophylaxis based on regarded early identified contacts of cases, prophylaxis based on vaccine use alone implies that systems are in place for HAV cases to vaccine use alone implies that systems are in place for HAV cases to be detected rapidly so that contacts can receive the vaccine within 7 be detected rapidly so that contacts can receive the vaccine within 7 days of exposuredays of exposure

• Vaccination during outbreaks has been sometimes successful and Vaccination during outbreaks has been sometimes successful and sometimes delayed in its effects. The coverage in those at higher sometimes delayed in its effects. The coverage in those at higher risk is a crucial point for the success of the strategyrisk is a crucial point for the success of the strategy

Problems and opportunities of use for hepatitis A Problems and opportunities of use for hepatitis A vaccine during outbreaks and post-exposure (2)vaccine during outbreaks and post-exposure (2)

OpportunitiesOpportunities

• Hepatitis A vaccine has been shown to be highly effective in Hepatitis A vaccine has been shown to be highly effective in pre-exposure prophylaxis. The relatively long incubation pre-exposure prophylaxis. The relatively long incubation period of hepatitis A is the basis for its use during outbreaksperiod of hepatitis A is the basis for its use during outbreaks

• The ‘number needed to treat’ with prophylaxis to prevent one The ‘number needed to treat’ with prophylaxis to prevent one case (depending upon prevalence of susceptibility, secondary case (depending upon prevalence of susceptibility, secondary attack rate following exposure, effectiveness of intervention attack rate following exposure, effectiveness of intervention and rate of clinical disease in the age group exposed) is less and rate of clinical disease in the age group exposed) is less than 20 in adults (less than 10 if secondary attack rate is ≥ 20). than 20 in adults (less than 10 if secondary attack rate is ≥ 20). In children, the number is greater (frequently asymptomatic In children, the number is greater (frequently asymptomatic infection)infection)

• Hepatitis A vaccine offers long-time protection. Its effect Hepatitis A vaccine offers long-time protection. Its effect outlasts the outbreak and might be successfully followed by outlasts the outbreak and might be successfully followed by the implementation of routine vaccination of children and/or the implementation of routine vaccination of children and/or adolescents in the affected areaadolescents in the affected area

Effectiveness of hepatitis A in a former Effectiveness of hepatitis A in a former frequently affected community - 9 years of frequently affected community - 9 years of follow-up follow-up (Kiryas Joel community of Monroe, NY)(Kiryas Joel community of Monroe, NY)

(Werzberger et al., (Werzberger et al., VaccineVaccine 2002; 20: 1699-1701) 2002; 20: 1699-1701) • Efficacy field trial of hepatitis A vaccine performed in 1991Efficacy field trial of hepatitis A vaccine performed in 1991

• Two epidemics, one lasting 3 years and the other 1.5 years Two epidemics, one lasting 3 years and the other 1.5 years during the 6.5 years preceding the vaccine trialduring the 6.5 years preceding the vaccine trial

• No case in any vaccine recipient later than day 16 after No case in any vaccine recipient later than day 16 after vaccinationvaccination

• Since 1991, 2-year olds routinely receive HA vaccineSince 1991, 2-year olds routinely receive HA vaccine

• Pre-vaccination pattern of frequent epidemics has Pre-vaccination pattern of frequent epidemics has disappeared, though sporadic cases were reported through disappeared, though sporadic cases were reported through 1997 in non-vaccinees1997 in non-vaccinees

• Cases continued to be reported in 4 sister communities Cases continued to be reported in 4 sister communities sharing a special bus route up to the end of 1999-2000sharing a special bus route up to the end of 1999-2000

Conclusions (1)Conclusions (1)• Hepatitis A vaccine is one of the most immunogenic vaccines Hepatitis A vaccine is one of the most immunogenic vaccines

availableavailable

• Its excellent efficacy in pre-exposure prophylaxis has been Its excellent efficacy in pre-exposure prophylaxis has been documented by several studiesdocumented by several studies

• Vaccination has been used in the course of outbreaks and for Vaccination has been used in the course of outbreaks and for the prevention of secondary cases. the prevention of secondary cases.

• Active prophylaxis usually shortened the course of outbreaks Active prophylaxis usually shortened the course of outbreaks where coverage of a well-defined target population was highwhere coverage of a well-defined target population was high

• No clinical trial on the effectiveness of HA vaccination during No clinical trial on the effectiveness of HA vaccination during outbreaks (in comparison with human normal immune outbreaks (in comparison with human normal immune gloubulin) is availablegloubulin) is available

• Although used in the past for post-exposure prophylaxis, Although used in the past for post-exposure prophylaxis, immune globulin preparations have probably decreased their immune globulin preparations have probably decreased their antibody concentrations, are difficult to get and are not well antibody concentrations, are difficult to get and are not well accepted due to their origin from human bloodaccepted due to their origin from human blood

Conclusions (2)Conclusions (2)• The only clinical trial of vaccine used for post-exposure The only clinical trial of vaccine used for post-exposure

prophylaxis showed good efficacy (about 80%). prophylaxis showed good efficacy (about 80%). Confidence intervals are wide, but high numbers of Confidence intervals are wide, but high numbers of subjects to be studied are very difficult to obtainsubjects to be studied are very difficult to obtain

• In communities experiencing recurrent epidemics the In communities experiencing recurrent epidemics the use of vaccination seems also justified by the high use of vaccination seems also justified by the high secondary attack rates and the consequent acceptable secondary attack rates and the consequent acceptable cost-effectiveness profilecost-effectiveness profile

• However, in areas where hepatitis A represents a public However, in areas where hepatitis A represents a public health problem, the implementation of routine health problem, the implementation of routine vaccination of children and/or adolescents seems, in the vaccination of children and/or adolescents seems, in the long term, the most reasonable way to put outbreaks long term, the most reasonable way to put outbreaks under controlunder control

Summary of actions when an outbreak Summary of actions when an outbreak occurs (occurs (“rapid is beautiful”“rapid is beautiful”))

1)1) Rapid identification of the sourceRapid identification of the source

2)2) Rapid identification of the population to be targeted by Rapid identification of the population to be targeted by vaccination (contacts of cases and people attending institutions vaccination (contacts of cases and people attending institutions where infection has occurred)where infection has occurred)

3)3) Quick information campaign on the infection, the way it is Quick information campaign on the infection, the way it is spread and the possibility of prevention by vaccination and by spread and the possibility of prevention by vaccination and by good hygiene practicesgood hygiene practices

4)4) Rapid creation of a task force in charge of the programmeRapid creation of a task force in charge of the programme

5)5) Rapid administration of the first vaccine dose to the target Rapid administration of the first vaccine dose to the target populationpopulation

6) Maintenance of records of vaccinated people 6) Maintenance of records of vaccinated people

7)7) Review of the campaign (initial number of cases, N° Review of the campaign (initial number of cases, N° immunised/target population, time to control the outbreak, N° immunised/target population, time to control the outbreak, N° of cases in vaccinees and their timing, N° of boosters)of cases in vaccinees and their timing, N° of boosters)