Mumps and Rubella Eliminated From Finland

Successful elimination of measles from some parts of the world, including Finland,¹ has encouraged the view that mumps and rubella might also be able to be eliminated, especially if trivalent measles-mumps-rubella (MMR) vaccine is included in national immunization programs. Finland launched such a program in November 1982.² The goal was to interrupt circulation of all 3 viruses, thereby eliminating indigenous measles, mumps, and rubella. Since mumps and rubella are diseases with severe impact,^{3 - 9} the benefits of their elimination were expected to outweigh the costs.

Before vaccines were available, the magnitude of the mumps problem was best reflected in the defense forces. Recruits arriving from rural areas often had no previous contact with mumps, and outbreaks were common. During World War II, 25% to 30% of recruits contracted clinical mumps,¹⁰ while an estimated 30% of infections remained asymptomatic. An especially formidable complication was epididymo-orchitis, experienced by 30% of these young men,¹¹ one fourth of whom experienced bilateral disease and a sterility risk of approximately 25%.^{4 ,11}

Among civilians (population, 5 million), the mean incidence of notified cases of mumps was 240 per 100,000 per year in the prevaccine era.¹² In 1971, nearly 23,000 cases were reported (Figure 1). More than 900 patients were hospitalized each epidemic year and some 650 person-years were lost from active life; 75% of these patients were aged 15 years or older. In Helsinki (population, 0.5 million) alone, physician-diagnosed mumps cases averaged 1019 per year. Complications and sequelae were common, and there was a relatively slow increase in natural antibodies with age: 40% to 70% of individuals were seropositive at 21 to 30 years of age. Among 658 sterile couples, 13% of the husbands and 23% of those with proven aspermia had had mumps orchitis—51% during compulsory military service.¹³

Especially common were meningitis and meningoencephalitis, some 600 cases being recorded during an epidemic year. Cerebrospinal pleocytosis developed in more than 50% of cases, symptomatic or not^{3 ,7} ; central nervous system involvement manifested in 28% of patients with clinical mumps.³ Most cases were mild, but deaths occurred.¹⁴ Mumps was also the most common cause of sensorineural hearing impairment in childhood.⁶ Permanent deafness was rare,³ but during military service, 4% of clinical mumps cases were associated with total deafness or significant hearing loss.⁵ Each epidemic year saw hundreds of patients with manifestations such as mastitis, oophoritis, thyroiditis, pancreatitis, or myocarditis.^{4 ,7}

Rubella had fewer country-specific features than mumps. Half of both sexes became seropositive before 10 years of age, and 90% had antibodies at 20 years of age.¹⁵ The mean incidence of notified cases was 104 per 100,000 per year.¹² Up to 50 cases of congenital rubella syndrome occurred in epidemic years. Rubella antibodies were over 3 times more common among children aged 6 months to 5 years with congenital hearing impairment than in controls (45% vs 13%).⁸ In a longitudinal survey in the United States, only 14% of patients with congenital rubella recovered without neurologic residuals at 9 to 12 years.⁹ Children with congenital rubella syndrome had an elevated death rate after 50 years of follow-up (standardized relative mortality rate, 6.0; 95% confidence interval [CI], 1.24-17.57).¹⁶

Helsinki averaged 840 cases of physician-diagnosed rubella per year, and hospitalizations occurred frequently, mostly for arthropathy. Rubella was associated with 2% of childhood encephalitis and rarely with death. Rubella in adults was associated with various chronic and bizarre disorders.¹⁷

When 30 recruits of the Finnish Army per day were falling ill during World War II, 128 men were given intracutaneously 0.1 mL of defibrinated blood drawn from patients with mumps.^{10 - 11} Another 67 recruits received intramuscularly 20 mL of serum pooled from 10 convalescent patients defervesced at least 14 days earlier; 146 nonimmunized recruits served as controls. Clinical mumps developed in 13% of blood recipients and in 15% of serum recipients vs 38% of controls. The efficacy was 65% (95% CI, 44%-79%) and 61% (95% CI, 29%-79%), respectively. Orchitis developed in 18% of blood recipients, in 10% of serum recipients, and in 29% of controls. Evidently, significant protection was induced by these preventive measures. No severe reactions were encountered.^{10 - 11}

The first vaccine study also took place in a military setting. Beginning in 1953, inactivated vaccine was given to certain recruits.^{14 ,18} The incidence of clinical mumps declined by 94%,¹⁴ and orchitis became 25 times rarer in vaccinees than nonvaccinees. These observations justified general immunization of recruits with a Finnish manufactured vaccine, and this policy continued from 1960 to 1986 (Figure 1). For years, Finland was the only country to protect its recruits against mumps.

Selective rubella vaccination of 11- to 13-year-old girls and mothers after delivery began with the Cendehill strain (Cendevax, SmithKline-RIT, Rixensart, Belgium) in 1975 (Figure 2). The aim was to prevent embryopathy without eradicating the virus from the community. The goal was not reached. At least 6% of primipara remained seronegative, and no decline in rubella embryopathy was observed. Selective monovalent vaccination continued until 1988, although the strain was changed to Wistar RA 27/3 (Rubeaten Berna, Swiss Serum and Vaccine Institute, Berne, Switzerland) in 1983. This strain is also a component of MMR vaccine.

A major change in vaccination policy took place in 1982 (Figure 1 and Figure 2). An entirely new goal was set: to interrupt circulation of all MMR viruses.² A trivalent MMR vaccine (MMR_II in the United States, Virivac in Scandinavia until 1998, Merck & Co Inc, West Point, Pa) was introduced into the national childhood immunization program.^{2 ,12} Selective rubella vaccination of girls and mothers who had recently delivered was soon discontinued (Figure 2), and inactivated mumps vaccine in defense forces was replaced by the Jeryl Lynn B strain (MMR vaccine).

The details of the new approach have been described previously.^{2 ,12 ,19} In short, MMR vaccination is administered by public health nurses at 1000 child health centers in the country, voluntarily and free of charge, at age 14 to 18 months and 6 years. Catch-up programs for intermediate ages and special risk groups were carried out initially. Military recruits have received 1 dose of the same MMR vaccine since 1986. To date, 3.5 million doses have been received by some 2 million individuals, 40% of the whole population.

Physicians, public health nurses, hospitals, and diagnostic virology laboratories are requested to report suspected cases of measles-mumps-rubella to the National Public Health Institute. Prior to the national project, the proportion of incorrect diagnoses among notified measles-mumps-rubella cases in relation to the rampancy of mumps and rubella was small. However, with the steep decline in incidence,¹² correct diagnosis became critical.²⁰ For this reason, serological confirmation has been required since 1987. For the past decade, epidemiological data have been collected individually from all cases. Modern techniques were added to the mumps and rubella serology.^{21 - 23}

Since the beginning of the project, the safety of the vaccine has been a key issue. A prospective, double-blind, cross-over study was carried out among 1162 twins.^{24 - 25} In addition, tolerability of allergic individuals to the MMR vaccine was studied.²⁶ We have also attempted to trace all long-term events potentially in a causal association with MMR vaccination. The first results of this 14-year prospective study have been published recently.²⁷

All the vaccines used through the years (Figure 1 and Figure 2) have proved safe.^{10 ,14 ,24 - 27} The twin study on MMR vaccination showed that vaccination-attributable events occurred in 6% overall, the clearest effect being fever exceeding 101.3°F (38.5°C) between days 6 and 14 after vaccination.²⁵ In terms of the long-term events, approximately 50% of the events associated with MMR vaccination were probably due, at least in part, to some other factor.²⁷ The most common event truly caused by vaccination is idiopathic thrombocytopenic purpura (incidence, ≥3.3 per 100,000 doses).²⁸ No death or permanent sequelae have been encountered.

The vaccination coverage has exceeded 95%. Antibodies elicited by MMR vaccination have persisted better against mumps²⁹ than rubella.³⁰ Fifteen years from the first MMR vaccination, one third (31%) of the primarily seronegative children showed antibody concentrations below 15 IU/mL (suggested protective level). For mumps, 18% of vaccinees showed concentrations lower than the cutoff level (2 SDs above the mean of negative controls).²⁹ Obvious vaccine failures of the mumps (and measles) components of MMR vaccine have been found, albeit rarely (H.P., unpublished data, 2000).

The impact of vaccination is indisputable. Figure 1 and Figure 2 list the number of notified (until 1986) and confirmed (1987-1999) cases of mumps and rubella in Finland since 1960. Mumps has decreased, except in 1987-1988 when an outbreak struck a northern community. The outbreak involved 75 cases, mostly high school students. Two probable vaccine failures were encountered. The outbreak was extinguished by giving MMR vaccine to some 500 individuals.

In 1996 there were 2 cases of endemic mumps, and the zero point was reached in 1997. The few cases still occurring have all been imported. The last case was encountered in 1999: a 26-year-old woman visited Mozambique and South Africa in October and was hospitalized in Finland for aseptic meningitis that was proven to be due to mumps; IgM serology was positive, and there was a 22-fold increase in IgG antibodies. No secondary cases emerged after any of the imported cases.

The decline in rubella incidence has mimicked that of mumps. Two outbreaks occurred in 1990 and 1991 (Figure 2), the first striking 4 towns in southwestern Finland, the second extending to the cities of Tampere and Helsinki. Both outbreaks probably had the same source.

Indigenous rubella disappeared in 1997 (Figure 2). However, 1 imported case occurred in 1997 and in 1998. The earlier case was a 12-year-old girl who had moved to Finland from St Petersburg. After developing a rash, the girl underwent serological testing because an epidemic was raging in St Petersburg; an indisputable IgG increase was found with IgM also being positive. The 1998 case was a 43-year-old man. After a visit to Estonia, macular rash and fever commenced within the likely incubation period. Positive IgM and IgG serology and low avidity of rubella-specific IgG, characteristic of recent infection,²³ proved the diagnosis. No secondary cases followed.

A large serosurvey that used the computerized data bank of the largest diagnostic virus laboratory in Finland (94,000 serum samples)¹⁵ found a total of 28 cases of congenital rubella syndrome between 1979 and 1986, but not 1 case after 1987. The rate of the serologically confirmed syndrome, once 18 cases per 100,000 births,¹⁵ has reached zero.

Finland is the first country to be documented to be free of indigenous mumps and rubella (and measles¹ ), and this has been achieved with safe and nonobligatory vaccinations. Claims that MMR vaccination might have harmed children by preventing their early exposure (especially to measles) and making them more prone to atopic and allergic diseases seem unjustified.³¹

Despite the indisputable benefits, there is a concern that waning vaccine-induced immunity will put the population at risk for a resurgence of disease. A mathematical model of protection induced by an immunization program using a single rubella vaccine dose^{32 - 33} suggested that—assuming 80% of 2-year-old children would be vaccinated, 90% of vaccinees would develop protective antibodies, and 1% per year would lose immunity—record low levels of congenital rubella syndrome would be reached within 20 to 25 years. By then the population at risk would be so large that an importation of virus would cause an exponential increase in embryopathy great enough to exceed the prevaccination level. Finland might be approaching that danger period.

Fortunately, 2 factors are in our favor. First, no mathematical model truly depicts the actual situation since underlying assumptions are not necessarily fulfilled.

Second, and more importantly, Finland relies on a 2-vaccine dose strategy. Our long-term follow-up studies indicate that antibodies decline over years, despite 2 vaccine doses,^{29 - 30} but we cannot interpret as yet the clinical relevance of this finding. We do not know at which point the danger—if there is a danger—of a substantial epidemic becomes real. We think that waning vaccine-induced immunity is a genuine phenomenon, especially in circumstances where natural boosters are totally lacking³⁴ (as now in Finland). One dose of MMR vaccine, even when successful for all components, does not necessarily induce lifelong immunity unless reinforced by subclinical infection³⁵ (natural boosters) or vaccination. The best we can do is to give 2 doses in the hope they will serve better than 1 dose. At least for measles, this approach seems well justified.³⁶

When infection pressure is low, the risk of vaccine failure also remains low, but we cannot expect this to always prevail. The recent resurgence of all measles-mumps-rubella diseases in the Western world is alarming. That no secondary cases followed any of the 6 imported cases of mumps or rubella in 1997 to 1999 in Finland supports the view that the (mostly) vaccine-induced immunity in the vicinity of the index cases has been sufficient.

In the United States in the 1980s,^{37 - 38} each dollar spent on mumps or rubella vaccination saved around $7 or $8, respectively, and vaccinating 1 million persons against mumps was likely to prevent more than 74,000 cases and 3 deaths.³⁸ A more recent estimation³⁹ was that combined MMR vaccination saves $18 in direct health care costs; this is 2.5-fold the price of traditional triple vaccine ($7). There are sound reasons for assuming that Finland has benefitted from the national MMR vaccination project.