May vaccinate adults to eliminate measles——Measles Eradication in China

LIAO Jun-lin，TAO Li-na，XU Zhi-yi

(1.Department of Surgery，Carver College of Medicine，University of Iowa，200 Hawkins Drive，Iowa City，IA 52242;2.Shanghai Municipal Center for Disease Control and Prevention，Shanghai 200336，China;3.School of Public Health，F(xiàn)udan University，Shanghai 200433，China)

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In 2001，the Measles Initiative was launched to set the stage for worldwide measles eradication.Encouraged by the experience in Americas，the World Health Organization (WHO)has embraced the Supplementary Immunization Activities (SIAs)as a core strategy for the control and eradication of measles［1－3］.Starting September 11，2010，the Ministry of Health of China (MOHC)conducted a nationwide campaign to vaccinate 96 million children in China within ten days“regardless of their immunization history”.

1 Two Doses of Measles Vaccine Build Sufficient Immunity

The measles vaccine is highly immunogenic.Chinese children are recommended first dose at 8 months old and second dose at 18 months.Many children receive their first dose at 12 months old or later.The first dose of measles vaccine induces immunity in 85% of the children if administered at 8 －9 months of age and in 95% if administered at or after 12 months of age.The second dose given at or after 18 months of age offers an efficacy of 95 －98%.With two doses combined，the overall efficacy is over 99%.There are reports where one single dose of measles vaccine may induce immunity up to 100%［4］.It has been demonstrated that induced immunity reaches 100% after two dose vaccination for measles［5］.Therefore，it has been suggested that even if a person's serology is negative，a third dose of measles vaccine is not needed［6］.The common method to detect measles antibody by enzymelinked immunosorbent assay (ELISA)may fail to reflect the protective antibody level［7－8］.

There are two strategies to deliver adequate doses to susceptible children，either through a routine immunization schedule or through national campaigns.With highly efficient health care delivery system like that of the United States，the routine immunization strategy is optimal.Because all children receive measles vaccines at recommended ages，population susceptibility is maintained at a constant low level.

However，the optimal strategy may fail to maintain population immunity to measles when the delivery system is inefficient.With such a system，a large proportion of the children fail to receive required doses at recommended ages.One dose schedule might also leave a significant proportion of vaccinated children susceptible to measles because of vaccine failure.By 1993，there were only three countries in Americas that had adopted two-dose schedules in their regular immunization program，United States，Cuba，and Costa Rica［9］.Over time，the number of susceptible children will accumulate，ultimately to a level at which measles outbreaks are possible.This was the situation in most of the countries in Americas in the early 1990s.

Facing frequent measles outbreak in the Americas，the Pan American Health Organization (PAHO)developed an alternative measles eradication strategy［10］.In this plan，one-time-only nationwide measles vaccination campaigns (termed Catch-up)for children 9 months to 14 years old were launched，followed by routine measles vaccination at 12 months of age (Keepup).Then every 4 years Follow-up campaigns similar to that of the Catch-up was launched targeting 1-to 4-year-old children，regardless of their immunization history.By year 2000，measles in the Americas was considered close to being eliminated，with an incidence rate of 1.86 per million.Apparently，the children in American countries under this alternative strategy had only received a maximum of two doses of measles vaccine—one through national campaigns and the other through routine immunization at the recommended age.

The alternative strategy largely shaped WHO policy in measles eradication.The Catch-up and Follow-up campaigns were translated into SIAs in WHO official documents.The two-dose strategy has been subsequently recognized as a cornerstone in guidance for combatting measles worldwide［1－2，11］.

Successful outbreak controls have documented the efficacy of two-dose strategy in other countries and regions.In 1994，the England and Wales health authority conducted an SIA campaign to forestall a projected outbreak of measles.At the time，the routine vaccination of children in England and Wales only included one dose［12］.Later，in 1997，Hong Kong predicted an outbreak of measles.An SIA campaign was carried out to improve population immunity.By that time，Hong Kong had already adopted the two-dose strategy for routine measles vaccination.Therefore，Hong Kong did not give a third dose to children who had two documented doses of measles vaccine.Hong Kong was successful in preventing measles outbreak［13］.

South Korea conducted a Catch-up campaign targeting 7-to 15-year-old children in 2001;although only 39% of the children had received a second dose of measles vaccine，Koreans did not subject their children to a third dose［14］.Yet South Korea was the first country in the WHO Western Pacific Region that was certified to have eradicated measles.

The theoretical as well as empirical evidence clearly indicate that two doses of measles vaccine are sufficient.Additional doses are redundant and should be avoided if possible.It is also exemplified by epidemiology data from within China.Beijing and Tianjin recommended three doses in their routine schedules.Tianjin had also carried out SIAs in 2008 targeting children 8 months to 14 years of age “regardless of their immunization and measles history”.Yet those two provinces ranked top three and four in the country in measles incidence in the first half of 2010.A third dose of measles vaccine adds little to individuals' immunity and the overall population immunity.

2 Preliminary Evaluation of 2010 Campaign

By late 1980s，the incidence rate of measles in China had decreased to 10 per 100，000.Thereafter，the incidence rate has been varying from 5 to 10 per 100，000 until 2008.In 2009，China experienced over 60% fall in measles incidence rate，to a record low of 3.95 per 100，000.Preliminary data for 2010 indicates an additional 27% reduction of incidence rate a further post campaign reduction of about 70% in the first 10 months of 2011.Post campaign mortality reduction is in the order of 55% with preliminary data.The 2010 measles campaign did bring down incidence rate and mortality as expected，however，it is still far above the professed goal of 1 incidence per million population［15］.

Since 1990s，China had already embarked on provincial and local SIAs as alternative strategy to expand measles vaccination in children.The Americas'experiences were duplicated，but the outcomes were less dramatic.Measles outbreaks have always been contained，but few provinces could claim eradication of measles.Measles outbreaks almost always come back to areas that had experienced temporary reprieve.In the last five years，provincial SIAs had intensified.From 2004 to 2009，up to 186 million doses of measles vaccine had already been administered to children by provincial SIAs，covering 27 of 31 provinces.The remaining four provinces either have well-organized routine immunization programs，or had conducted SIAs earlier，or both.The 2010 campaign may be simply one more such campaign that only provides temporary reprieve.

China had initiated a two-dose schedule in 1987.The vaccination rate was estimated as 70% nationally in 1995.In the 2000s，routine measles vaccination had been reported as 85% for migrating population and 95% for non-migrating population［16］.It can be estimated that at least 70% of the children targeted in the 2010 campaign have already received two doses or more of measles vaccine.Therefore，at least 70% (67 million)of the 96 million doses of measles vaccine would be considered as unnecessary or wasted.

Twenty-one provinces conducted SIA campaigns in the last two years.Guangxi had conducted a Catch-up campaign in 2009，and all children 8 months to 14 years were to be vaccinated yet again in the 2010 national campaign.Beijing and Shanghai are the most economically developed areas in China，with the best infrastructure to deliver routine immunization.Both provinces include three doses in their routine immunization.Yet both provinces were included to deliver an additional dose of measles vaccine to all children 8 months to 14 years old.This would be the fourth dose for many.

Indiscriminate vaccination of children may be justified by the lack of documentation of earlier vaccinations.It has been estimated that in Shanghai，98% of the children have complete immunization records.Other areas may report almost perfect recordkeeping［17］.The time and effort saved at checking immunization records with indiscriminate vaccination must be weighed against time and effort at redundant vaccinations.When the clinics were overwhelmed by vaccinating all the children regardless of their immunization status，they were less likely to identify those who had always been left out of such campaigns and remained unvaccinated.When the majority of targeted children were known to have received at least two doses of measles vaccine，the decision to administer additional unnecessary doses may be unethical because vaccines are not risk-free.

3 The Change Profile of Susceptibility

Countries in the Americas，as well as South Korea，experienced spectacular success in combating measles.The incidence rate in PAHO countries started to consistently decline in 1990s.The incidence rate decreased to 6.1 per 1，000，000 in 1995 and 1.7 per 1，000，000 in 1996.The drastic reduction in incidence rate was achieved with an overall 80% vaccination rate and two-dose strategy［10］.South Korea reported a measles incidence rate of 118 per 100，000 in 2000 ～2001［14］，at least five times the incidence rates in China by late 1980s.By simply conducting one national SIA targeting a subgroup of children，South Korea achieved measles eradication within one year.

Why has the incidence of measles in China persisted at levels of 5 to 10 per 100，000 with a 90% vaccination rate of children?The cases of Beijing and Tianjin provinces may be most telling.In both provinces，the incidence rates surpassed 10 per 100，000 in the first six months of 2010，and in both provinces over 50% of cases occurred in people 15 years and older(see Figure 1).Nationally，the age group from 15 to 34 years old comprises 23% of all measles cases in 2010.More than 53% of the cases occurred in populations not covered by any immunization program.Preliminary data from Shanghai post 2010 campaign indicates that 64% of cases occurred in those populations in 2011.

The Beijing and Tianjin experiences are not new.For example，in PAHO countries in 1997，the number of measles cases jumped up to 53，683 from the record low of 2，109 in 1996.About 80% of those cases were from Sao Paulo，Brazil.Of the outbreaks in Sao Paulo，71% of cases occurred in people aged 20 years and older［18］.The majority of cases occurred in young adults born in the period when vaccination programs were launched in the state.

Measles is a childhood disease.Earlier in 20th century，when vaccination was not available，95% of measles cases were children 14 years and younger［19］.With frequent exposure to measles outbreaks，children develop immunity as they reach adulthood.When all children were vaccinated over a short period of time，measles virus circulation is interrupted because the overall population immunity is high.However，if the children were vaccinated but the vaccination rate was not sufficiently high，measles virus circulation is contained but not interrupted.When this generation of children grows up，the susceptibility profile of the population is drastically different.

The immunity against measles in birth cohorts of adults typically follows a“”shaped curve，with the low level of immunity in birth cohorts following the launch of immunization programs［20］.The low-level-ofimmunity cohorts are the ones that fall below what is required to interrupt measles virus circulation.It could be indicated by below a strikethrough line in the letter“U”.The earlier cohorts develop immunity from natural infection.The later cohorts develop immunity from increasing coverage in vaccination.Even though China had launched its measles vaccine in 1965，the earlier vaccines provided limited coverage throughout the country and the population was largely developing immunity through natural infections.In developed area in China，low level of immunity occurred in the 1980 ～1990 cohorts［21］，about 15 years later than the U.S.cohort of 1967 ～1976.In other areas，low level of immunity might occur with later cohorts［22］.

The overall population immunity may be sufficient to stop measles if the low-level-of-immunity cohorts span limited number of years and the actual level is not too low.China had a long history of suboptimal vaccination rates in 1980s and 1990s.The nadir point may reach as low as 60% of the birth cohorts with immunity to measles［23］and the low level of immunity cohorts may span more than 20 years［22］.The 1970 ～1990 birth cohorts are baby boomers and together they comprise one-third of Chinese population.Even if the average immunity level sustained at 80% and all other age groups at 100%，the population immunity is below 95%，which the Centers for Disease Control and Prevention of China (CDCPC)estimates as required to interrupt measles virus circulation.

The lack of immunity among young adults further affects the passive immunity in their offspring during infancy.Infants are normally protected by maternal antibody before they are vaccinated at 8 months old.The low level of immunity in the 1970 ～1990 birth cohorts results in a larger proportion of infants unprotected from zero to eight months of age.Additionally，maternal antibody is proportional to antibody level in their mothers.Maternal antibody titer from the mothers with measles history may be four times as high as that from vaccinated mothers［24］.The passive immunity disappears over time，and higher maternal antibody titer has a longer protection period and provides stronger protection.The maternal antibody from mothers in the cohorts of the pre-vaccine era may provide protection from measles up to 7.5 times that of antibody from mothers from post-vaccine era［25］.Infants are the most susceptible in all age groups in China，accounting for 21% of all measles cases nationally in 2010.

The emergence of babies from vaccinated mothers pushes for higher population immunity level in existing population required to interrupt measles virus circulation.Furthermore，the unique socio-economic structure of Chinese society puts an additional requirement on population immunity level.One of the legacies of Mao era is the Population Registration (Hukou in Chinese)System.This system prevented any unauthorized migration and allowed the government tight control over its citizens.In post-Mao era，this system no longer restricts the migration of the population;however，it creates a permanent tie for the migrating population with their birth places.Social benefits are distributed through the location of registration and citizens may need to pay taxes and hold nontransferable property such as land in location of registration.The permanent tie not only creates more traffic between“temporary”residence and location of registration，but also lowers the loyalty of the migrating population to their“temporary”residence.Therefore，hundreds of millions of workers travel annually across the nation seeking economic opportunities elsewhere and returning to their registration places.Those workers come mostly from rural areas with potentially low vaccination rates.When you have a susceptible population on the move，it requires high population immunity to interrupt measles virus circulation.

The migration of Chinese population determines the occasional measles outbreak pattern.The outbreaks of measles in China have not been confined in a particular area in China.High incidence is always followed by low incidence，as if the outbreaks of measles have been travelling in China randomly across different regions (see Figure 2).The unvaccinated adult population carries the measles virus around the country.When the virus reaches a pocket of susceptible population，it causes an outbreak that would subsequently immunize them.The outbreak then stops at the boundary of this pocket of population and disappears，only to reemerge somewhere else.

The migrating pattern of measles outbreaks is almost random.The incidence rate of measles has followed such a national pattern since 1990s.No matter how hard the provincial health authorities have tried to improve the vaccination rate among children，their provinces may be hit with outbreaks in some years.Tianjin children had mostly been vaccinated four times，but the province has been hit hard in 2010 with measles incidence rate 162 per 1000，000.Over 80%cases were young adults，adults，and infants who had not reached the age for vaccination.

4 Vaccinating Adults May Be Required to Eradicate Measles in China

The Chinese educational system is rigid and children are far less mobile than their parents.Children may be asked to pay extra cost to transfer to schools not in their registration area.It is not uncommon for children to be left with their grandparents in order to attend designated schools.Vaccinating a mobile，young adult may entail much greater benefits in interrupting measles virus circulation than vaccinating a child.

The susceptible young adult are in birth cohorts from 1970 to 1995，with total population of 539 million.Even though vaccination rate in 1995 was only 70% nationally，the birth cohorts in early 1990s may have been vaccinated in later SIA campaigns.The overall vaccination rate in this group may be higher than 90% as suggested by antibody seropositive rate［21，26］.For the birth cohorts in early 1970s，poor documentation might increase the need for vaccines should they be considered for supplemental vaccination.With sera antibody profile as guidance we could estimate that 50% of the population in this group requires vaccination.With a straight-line projection of proportions of young adults requiring supplemental vaccination for the birth cohort in between，we estimate that about 161 million doses of measles vaccine would be required to cover young adults 20 ～40 years old in 2010.

During the period of 2004 ～2009，186 million doses of measles vaccine were indiscriminately administered to children，with the majority of them having already completed the required two doses.Potentially half of those vaccines were wasted if a discriminate strategy were adopted to vaccinate only children without documented two doses of vaccine.Combined with the 2010 campaign，the wastage could be higher than 160 million doses，sufficient to cover the unvaccinated young adults for a Catch-up campaign.

Based on serological evidence，20 ～30% of this group of young adults might already have immunity.With 95% efficacy in measles vaccine，we may expect up to 115 million young adults to be converted to immune status，boosting whole population immunity by 8.7%.As a comparison，with the existing measles incidence rate，natural infection of measles develops immunity in less than 21，000 adults annually.The increase in population immunity level is about 0.0016%per year，completely negligible.

5 Conclusion

China had committed to measles eradication and has published a seven-year strategic plan for 2006 ～2012［15］.The plan was modeled after WHO stipulations and clearly states the two －dose strategy for subsequent operations.The strategy had been proven in many countries that have achieved measles elimination.Three-dose strategy for children both in routine immunization and in SIAs has failed to control measles outbreaks in several provinces and is likely to fail again on a national level.

SIAs targeting young adults may be necessary to interrupt measles virus circulation in the country.Vaccinating young adults will improve population immunity，prevent young adults spreading virus around the country，and boost passive immunity in infants.

China’s obsession with over-vaccinating children may be based on wrong assumptions.In a guidance document from the WHO，United Nations Children’s Fund，and CDCPC［27］，it was determined that“in the Americas，susceptibility in adults had not been able to sustain further measles transmission”and outbreaks among adults“do not represent a threat to elimination if they die out naturally due to very high population immunity among younger age cohort”.However，it did warn that“susceptible adults may sustain limited，low level transmission”.It is high time for China to re-evaluate this latter possibility.

The China experience may also serve as a wakeup call to other countries.Measles eradication has to be rapidly implemented and suboptimal vaccination of children for a long period of time will create a susceptible adult population in the future.A large susceptible adult population can support continued low-level measles virus circulation.

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