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Measles, mumps and rubella: Present and future immunisation policy
Public Health (1988), 102, 317-321
Measles, Mumps and Rubella: Present and Future Immunisation Policy Elizabeth Miller
Public Health Laboratory Service, Communicable Disease Surveillance Centre, 61 Colindale Avenue, London NW9 5EO
Selective rubella vaccination has achieved a substantial reduction in the incidence of rubella infection in pregnancy and its inevitable sequelae of congenital rubella syndrome (CRS) births and therapeutic abortions. However, recent epidemiological evidence has shown that the number of infections among the 2-3% of pregnant women still susceptible remains unacceptably high and that there is no prospect of eliminating CRS with selective vaccination alone. The current policy will therefore be augmented by mass rubella vaccination using a combined measles/mumps/rubella (MMR) vaccine. The aim is to prevent the circulation of rubella thereby protecting susceptible pregnant women from exposure. The target will be to vaccinate every child of both sexes for whom there is no valid contradiction. As part of this new initiative, measures are being taken to increase professional commitment and to make Districts accountable to DHSS for their immunisation performance. Surveillance of the effect of the M M R programme will include monitoring of vaccine uptake, disease incidence and age-specific antibody prevalence to measles, mumps and rubella. Surveillance data will be used to guide the new policy towards the goal of elimination of measles, mumps, rubella and CRS in the UK.
Present Rubella Policy Aim In the U K , rubella vaccine was introduced in 1970 for girls aged 11-14 years and for seronegative w o m e n o f childbearing age in 1974. In 1983, the aim o f the vaccination policy was defined as 'the control and ultimate elimination o f congenital rubella infection and therefore o f all rubella defects'. ~ Neither the reduction o f natural rubella, nor the development o f herd i m m u n i t y was part o f the strategy; indeed the continued circulation o f rubella virus was considered a necessary c o n t r i b u t i o n to maintaining the level o f i m m u n i t y in w o m e n o f childbearing age. Evaluation o f selective vaccination In 1972 vaccine acceptance in schoolgirls was only 71% 2 b u t by 1985 it had risen to 86%.3 In m a n y areas it is n o w over 90%, but it is unlikely, even with m a x i m u m effort to exceed 95%. Studies o f vaccine u p t a k e by seronegative adult w o m e n have s h o w n implementation o f p o s t - p a r t u m vaccination to be variable with between 10% and 90% vaccinated depending on hospital policy. 4'5 Vaccination o f susceptible w o m e n identified by p r e - p r e g n a n c y screening is also incomplete less than two thirds vaccinated even with active follow up by the screening laboratory. 4 Despite these shortcomings the effect o f selective vaccination on rubella susceptibility has © The Society of Community Medicine, 1988
318
E. Miller
been considerable. 4's'6 Surveillance by the Public Health L a b o r a t o r y Service (PHLS) has shown that only 2~4% of pregnant women are susceptible compared with about 10% of adult males; susceptibility is lower in parous than nulliparous women confirming the effect of post-partum vaccination. Current antenatal serological data from four of the PHLS laboratories are shown in Table I. However, continued surveillance of the Manchester antenatal population (about 40,000 pregnancies a year) has shown no sustained decline in susceptibility since 19835 and it would appear that selective vaccination has now achieved its main effect. Table I
Rubella susceptibility in pregnant women in 4 PH laboratories 1986/7 Negative
Laboratory
No. tested
Ashford Manchester Leeds Reading
No.
%
Nullip. Parous
7,849 10, ! 82
214 81
2.7
Nullip. Parous
26,805 34,128
939 588
3.6
Nullip. Parous
13,230 7,324
337 121
2.5
Nullip. Parous
3,954 5,101
93 63
2.4
107,853
2,436
2.3
Total
0.8
1.7 1.7 1.2
600 500 o r~ 4 0 0
"5 30o "~ 200 Z
100 1979
1978
t
124
t980
_3
1981
1982
Cases of CRS
1983
t
1984
52
1405
Rubella terminations
408
2220
Infections in pregnancy reported to CDSC
738
I
t
Figure 1 Number of laboratory confirmed rubella infections reported to CDSC and number of cases of congenital rubella, rubella terminations and infections in pregnancy during the 1978/79 and 1983/84 outbreaks.
Measles, Mumps and Rubella Immunisation
319
The reduction in susceptibility in women of childbearing age has been reflected in a welcome reduction in the incidence of rubella in pregnancy. 6 Nevertheless the number of women infected each year is still unacceptably high. Of the 2,436 susceptible antenatal patients identified by the 4 PHLS laboratories over the period January 1986 to September 1987 (Table I), 42 (1.7%) were known to have caught rubella during their pregnancy. The total number o f confirmed infections in pregnancy for England and Wales during 1986 was 196; a further 155 cases have been reported by PHLS laboratories during the first ten months o f 1987. The number of women infected is directly determined by the prevalence of infection among young children; in consequence the proportion of parous women among those infected is disproportionately high. 7 Many such pregnancies are terminated when infection is diagnosed in time, but when this is not possible, congenital rubella syndrome (CRS) may result; on average, there are ten therapeutic abortions for every notified case of CRS (Figure 1). Clearly, while rubella continues to circulate among young children, infection of susceptible pregnant women is inevitable.
Future Policy Aim To achieve elimination of CRS the Joint Committee on Vaccination and Immunisation has now recommended that the existing policy should be reinforced by the mass rubella vaccination of young children. Under the new policy, measles vaccine currently given in the second year of life will be replaced by a combined measles, mumps rubella vaccine ( M M R ) with the aim of eliminating these three diseases. For this, a high vaccine uptake in the i-2 year old age group is essential. The target uptake already set for measles vaccine at this a g e - 9 0 % by 19908- must therefore become the target for M M R vaccine. For the first 3 or 4 years of the programme, children who have already received measles vaccine will be offered M M R before school entry when they receive their diphtheria/tetanus booster. It is planned to continue the selective rubella vaccination of schoolgirls and adult women until the elimination of rubella has been demonstrated. A 2 stage-policy in which M M R vaccine is routinely given twice - once during the second year of life and again to all children at twelve years as in Sweden 9 - i s not planned at present. Results of a large age-stratified serological survey carried out by the PHLS during 1986/87 m have shown that more than 90% of children are already immune to measles and mumps by the age of 12; about 3 in 4 children are immune to rubella and under the existing programme half (the girls) are vaccinated. There would, therefore, be little impact on the epidemiology o f measles, mumps or rubella by vaccinating 12 year olds at the moment. The major thrust o f the new policy must be directed toward achieving high levels of immunity in the pre-school population.
Implementation What can be done to ensure that M M R vaccine uptake is higher than that hitherto achieved for measles vaccine in the UK? It has been suggested that, together with the introduction of M M R vaccine, legislation should also be introduced requiring evidence of immunisation for entry to school. H The success of school entry laws has been demonstrated in the USA ~2 but high uptake has also been achieved elsewhere, including parts of the UK, without recourse to legislation. ~3Adequate funding for local staff and resources must be provided, but this b y itself is not sufficient; increased professional commitment towards vaccination is
320
E. Miller
also essential. The first step towards this has been taken by the designation in each District of 'responsible officers' - named individuals accountable to the D H S S for the local immunisation p r o g r a m m e both in Health Authority clinics and through general practitioners. Two meetings have already taken place between medical officers of the D H S S and the District representatives at which immunisation problems and the plans for the introduction o f M M R vaccine have been discussed. As part of this new initiative, Health Authorities will have an obligation, although not a statutory requirement, to ensure that every child has received appropriate vaccination by the time of entry to school. Surveillance
As an integral part o f the new policy, special surveillance schemes are being set up to monitor the immediate and long term effects of the programme. A system for providing accurate and up-to-date information on vaccine uptake is already in operation in Districts where appropriate computerised records are available. ~4 This scheme will allow the percentage vaccination o f each 3 monthly birth cohort of children to be monitored and will provide an early indication of the response to the new programme. Surveillance of the effect of M M R vaccine on disease incidence will require the present list of notifiable diseases to be extended to include rubella and mumps. Additional information on trends in disease incidence is available from reports to the Communicable Disease Surveillance Centre of laboratory confirmed m u m p s and rubella infections. L a b o r a t o r y data shows m u m p s to be the most c o m m o n cause of viral meningoencephalitis in children, ~5 resulting in a b o u t 1,000 hospital admissions each year. A substantial decline in the number of young children admitted to hospital with mumps-related complications can therefore be expected following the introduction of M M R vaccine. F o r rubella, the most immediate measure o f the impact of mass vaccination is likely to be the n u m b e r of laboratory confirmed infections in pregnancy reported to CDSC. Continued surveillance o f rubella susceptibility in the antenatal population is clearly essential. In addition, the effect of the new p r o g r a m m e on age-specific antibody prevalence to measles, m u m p s and rubella will also be monitored. It is planned to test at least 4,000 samples each year from the 1-15 year old age groups; base line data across all ages for 1986/87 have already been obtained.~° Because of the ethical problems involved in bleeding children, sera submitted to P H L S or N H S laboratories for diagnostic or biochemical investigations are being used. Serological surveillance will show the effect o f the policy on immunity levels in different age groups; in particular it will indicate whether a sufficient number of individuals are entering adult life susceptible to the three diseases to warrant a two-stage M M R policy at some later date. It has been postulated, using predictions from mathematical models, that if M M R vaccine uptake is less than 60 70%, infection in those that remain unvaccinated may be deferred until adult life; in the case o f rubella it has been suggested that this could result in a possible increase in C R S . 16 Although such effects would not be apparent until a b o u t 20 years time, appropriate surveillance must be instituted at the outset. It should be emphasised however that there are no plans to stop selective rubella vaccination until the elimination of rubella has been achieved. The introduction of M M R vaccine provides the opportunity to demonstrate that effective immunisation p r o g r a m m e s can be implemented in the U K without recourse to legislation. The objective o f eliminating an infectious disease is ambitious and one which presents an exciting challenge to preventive medicine; with over 82,000 cases o f measles notified in England and Wales in 1986, there is still a long way to go.
Measles, Mumps and Rubella Immunisation
32!
References 1. Dudgeon, J. A. (1983). Immunisation policies. British Medical Journal, 286, 1511. 2. Peckham, C. S , Marshall, W. C. & Dudgeon, J. A. (1977). Rubella vaccination of schoolgirls: factors affecting uptake. British Medical Journal, i, 760-761. 3. Department of Health and Social Security. (1986). Rubella vaccination in schoolgirls. London: HMSO (SBL 607). 4. Miller, C. L., Miller, E. Sequeira P. J. L., Cradock-Watson, J. E., Longson, M. & Wiseberg, E. C. (1985). Effect of selective vaccination on rubella susceptibility and infection in pregnancy. British Medical Journal, 291, 1398-1401. 5. Miller, C. L., Miller, E. & Waight, P. A. (1987). Rubella susceptibility and the continuing risk of infection in pregnancy. British Medical Journal, 294, 1277-1278. 6. Miller, C. L. & Miller, C. (1985). Rubella vaccination in the UK: Time for a complete strategy. Lancet, ii, 732. 7. Miller, E., Cradock-Watson J. E. & Pollock, T. M. (1982). Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet, ii, 781-784. 8. Department of Health and Social Security. (1984). Measles Immunisation. London: DHSS, Health Notice HN(84)19, HN(FP)(84)23. 9. Christenson, B., Bottiger, M. & Heller, L. (1983). Mass vaccination programme aimed at eradicating measles, mumps and rubella in Sweden: first experience. British Medical Journal, 287, 389-391. 10. Miller, C. L., Miller, E., Begg, N. T., Morgan-Capner, P. (1987). Rubella vaccination policy: a note of reassurance. Lancet, ii, 210. 11. Anderson, R. M. & Grenfell, B. T. (1985). Control of congenital rubella syndrome by mass vaccination. Lancet, ii, 827. 12. Robbins, K. B., Branding Bennett, A. D. & Hinman, A. R. (1981). Low incidence of measles: association with enforcement of school immunisation laws. American Journal of Public Health, 71,270-274. 13. Walker, D., Carter, H. & Jones, I. (1986). Measles, mumps and rubella: the need for a change of policy. British Medical Journal, 292, 1501-1502. 14. Gill, O. N. & Begg, N. T. (1987). Public Health Laboratory Service, Communicable Disease Surveillance Centre, Communicable Disease Report 87/12, 3 4 . 15. Noah, N. D. & Urquhart, A. M. (1980). Virus meningitis and encephalitis in 1979. Journal of Infection, 2, 379-383. 16. Anderson, R. M. & May, R. M. (1983). Two-stage vaccination programme against rubella. Lancet, ii, 14161417.
Measles, Mumps and Rubella: Present and Future Immunisation Policy Elizabeth Miller
Public Health Laboratory Service, Communicable Disease Surveillance Centre, 61 Colindale Avenue, London NW9 5EO
Selective rubella vaccination has achieved a substantial reduction in the incidence of rubella infection in pregnancy and its inevitable sequelae of congenital rubella syndrome (CRS) births and therapeutic abortions. However, recent epidemiological evidence has shown that the number of infections among the 2-3% of pregnant women still susceptible remains unacceptably high and that there is no prospect of eliminating CRS with selective vaccination alone. The current policy will therefore be augmented by mass rubella vaccination using a combined measles/mumps/rubella (MMR) vaccine. The aim is to prevent the circulation of rubella thereby protecting susceptible pregnant women from exposure. The target will be to vaccinate every child of both sexes for whom there is no valid contradiction. As part of this new initiative, measures are being taken to increase professional commitment and to make Districts accountable to DHSS for their immunisation performance. Surveillance of the effect of the M M R programme will include monitoring of vaccine uptake, disease incidence and age-specific antibody prevalence to measles, mumps and rubella. Surveillance data will be used to guide the new policy towards the goal of elimination of measles, mumps, rubella and CRS in the UK.
Present Rubella Policy Aim In the U K , rubella vaccine was introduced in 1970 for girls aged 11-14 years and for seronegative w o m e n o f childbearing age in 1974. In 1983, the aim o f the vaccination policy was defined as 'the control and ultimate elimination o f congenital rubella infection and therefore o f all rubella defects'. ~ Neither the reduction o f natural rubella, nor the development o f herd i m m u n i t y was part o f the strategy; indeed the continued circulation o f rubella virus was considered a necessary c o n t r i b u t i o n to maintaining the level o f i m m u n i t y in w o m e n o f childbearing age. Evaluation o f selective vaccination In 1972 vaccine acceptance in schoolgirls was only 71% 2 b u t by 1985 it had risen to 86%.3 In m a n y areas it is n o w over 90%, but it is unlikely, even with m a x i m u m effort to exceed 95%. Studies o f vaccine u p t a k e by seronegative adult w o m e n have s h o w n implementation o f p o s t - p a r t u m vaccination to be variable with between 10% and 90% vaccinated depending on hospital policy. 4'5 Vaccination o f susceptible w o m e n identified by p r e - p r e g n a n c y screening is also incomplete less than two thirds vaccinated even with active follow up by the screening laboratory. 4 Despite these shortcomings the effect o f selective vaccination on rubella susceptibility has © The Society of Community Medicine, 1988
318
E. Miller
been considerable. 4's'6 Surveillance by the Public Health L a b o r a t o r y Service (PHLS) has shown that only 2~4% of pregnant women are susceptible compared with about 10% of adult males; susceptibility is lower in parous than nulliparous women confirming the effect of post-partum vaccination. Current antenatal serological data from four of the PHLS laboratories are shown in Table I. However, continued surveillance of the Manchester antenatal population (about 40,000 pregnancies a year) has shown no sustained decline in susceptibility since 19835 and it would appear that selective vaccination has now achieved its main effect. Table I
Rubella susceptibility in pregnant women in 4 PH laboratories 1986/7 Negative
Laboratory
No. tested
Ashford Manchester Leeds Reading
No.
%
Nullip. Parous
7,849 10, ! 82
214 81
2.7
Nullip. Parous
26,805 34,128
939 588
3.6
Nullip. Parous
13,230 7,324
337 121
2.5
Nullip. Parous
3,954 5,101
93 63
2.4
107,853
2,436
2.3
Total
0.8
1.7 1.7 1.2
600 500 o r~ 4 0 0
"5 30o "~ 200 Z
100 1979
1978
t
124
t980
_3
1981
1982
Cases of CRS
1983
t
1984
52
1405
Rubella terminations
408
2220
Infections in pregnancy reported to CDSC
738
I
t
Figure 1 Number of laboratory confirmed rubella infections reported to CDSC and number of cases of congenital rubella, rubella terminations and infections in pregnancy during the 1978/79 and 1983/84 outbreaks.
Measles, Mumps and Rubella Immunisation
319
The reduction in susceptibility in women of childbearing age has been reflected in a welcome reduction in the incidence of rubella in pregnancy. 6 Nevertheless the number of women infected each year is still unacceptably high. Of the 2,436 susceptible antenatal patients identified by the 4 PHLS laboratories over the period January 1986 to September 1987 (Table I), 42 (1.7%) were known to have caught rubella during their pregnancy. The total number o f confirmed infections in pregnancy for England and Wales during 1986 was 196; a further 155 cases have been reported by PHLS laboratories during the first ten months o f 1987. The number of women infected is directly determined by the prevalence of infection among young children; in consequence the proportion of parous women among those infected is disproportionately high. 7 Many such pregnancies are terminated when infection is diagnosed in time, but when this is not possible, congenital rubella syndrome (CRS) may result; on average, there are ten therapeutic abortions for every notified case of CRS (Figure 1). Clearly, while rubella continues to circulate among young children, infection of susceptible pregnant women is inevitable.
Future Policy Aim To achieve elimination of CRS the Joint Committee on Vaccination and Immunisation has now recommended that the existing policy should be reinforced by the mass rubella vaccination of young children. Under the new policy, measles vaccine currently given in the second year of life will be replaced by a combined measles, mumps rubella vaccine ( M M R ) with the aim of eliminating these three diseases. For this, a high vaccine uptake in the i-2 year old age group is essential. The target uptake already set for measles vaccine at this a g e - 9 0 % by 19908- must therefore become the target for M M R vaccine. For the first 3 or 4 years of the programme, children who have already received measles vaccine will be offered M M R before school entry when they receive their diphtheria/tetanus booster. It is planned to continue the selective rubella vaccination of schoolgirls and adult women until the elimination of rubella has been demonstrated. A 2 stage-policy in which M M R vaccine is routinely given twice - once during the second year of life and again to all children at twelve years as in Sweden 9 - i s not planned at present. Results of a large age-stratified serological survey carried out by the PHLS during 1986/87 m have shown that more than 90% of children are already immune to measles and mumps by the age of 12; about 3 in 4 children are immune to rubella and under the existing programme half (the girls) are vaccinated. There would, therefore, be little impact on the epidemiology o f measles, mumps or rubella by vaccinating 12 year olds at the moment. The major thrust o f the new policy must be directed toward achieving high levels of immunity in the pre-school population.
Implementation What can be done to ensure that M M R vaccine uptake is higher than that hitherto achieved for measles vaccine in the UK? It has been suggested that, together with the introduction of M M R vaccine, legislation should also be introduced requiring evidence of immunisation for entry to school. H The success of school entry laws has been demonstrated in the USA ~2 but high uptake has also been achieved elsewhere, including parts of the UK, without recourse to legislation. ~3Adequate funding for local staff and resources must be provided, but this b y itself is not sufficient; increased professional commitment towards vaccination is
320
E. Miller
also essential. The first step towards this has been taken by the designation in each District of 'responsible officers' - named individuals accountable to the D H S S for the local immunisation p r o g r a m m e both in Health Authority clinics and through general practitioners. Two meetings have already taken place between medical officers of the D H S S and the District representatives at which immunisation problems and the plans for the introduction o f M M R vaccine have been discussed. As part of this new initiative, Health Authorities will have an obligation, although not a statutory requirement, to ensure that every child has received appropriate vaccination by the time of entry to school. Surveillance
As an integral part o f the new policy, special surveillance schemes are being set up to monitor the immediate and long term effects of the programme. A system for providing accurate and up-to-date information on vaccine uptake is already in operation in Districts where appropriate computerised records are available. ~4 This scheme will allow the percentage vaccination o f each 3 monthly birth cohort of children to be monitored and will provide an early indication of the response to the new programme. Surveillance of the effect of M M R vaccine on disease incidence will require the present list of notifiable diseases to be extended to include rubella and mumps. Additional information on trends in disease incidence is available from reports to the Communicable Disease Surveillance Centre of laboratory confirmed m u m p s and rubella infections. L a b o r a t o r y data shows m u m p s to be the most c o m m o n cause of viral meningoencephalitis in children, ~5 resulting in a b o u t 1,000 hospital admissions each year. A substantial decline in the number of young children admitted to hospital with mumps-related complications can therefore be expected following the introduction of M M R vaccine. F o r rubella, the most immediate measure o f the impact of mass vaccination is likely to be the n u m b e r of laboratory confirmed infections in pregnancy reported to CDSC. Continued surveillance o f rubella susceptibility in the antenatal population is clearly essential. In addition, the effect of the new p r o g r a m m e on age-specific antibody prevalence to measles, m u m p s and rubella will also be monitored. It is planned to test at least 4,000 samples each year from the 1-15 year old age groups; base line data across all ages for 1986/87 have already been obtained.~° Because of the ethical problems involved in bleeding children, sera submitted to P H L S or N H S laboratories for diagnostic or biochemical investigations are being used. Serological surveillance will show the effect o f the policy on immunity levels in different age groups; in particular it will indicate whether a sufficient number of individuals are entering adult life susceptible to the three diseases to warrant a two-stage M M R policy at some later date. It has been postulated, using predictions from mathematical models, that if M M R vaccine uptake is less than 60 70%, infection in those that remain unvaccinated may be deferred until adult life; in the case o f rubella it has been suggested that this could result in a possible increase in C R S . 16 Although such effects would not be apparent until a b o u t 20 years time, appropriate surveillance must be instituted at the outset. It should be emphasised however that there are no plans to stop selective rubella vaccination until the elimination of rubella has been achieved. The introduction of M M R vaccine provides the opportunity to demonstrate that effective immunisation p r o g r a m m e s can be implemented in the U K without recourse to legislation. The objective o f eliminating an infectious disease is ambitious and one which presents an exciting challenge to preventive medicine; with over 82,000 cases o f measles notified in England and Wales in 1986, there is still a long way to go.
Measles, Mumps and Rubella Immunisation
32!
References 1. Dudgeon, J. A. (1983). Immunisation policies. British Medical Journal, 286, 1511. 2. Peckham, C. S , Marshall, W. C. & Dudgeon, J. A. (1977). Rubella vaccination of schoolgirls: factors affecting uptake. British Medical Journal, i, 760-761. 3. Department of Health and Social Security. (1986). Rubella vaccination in schoolgirls. London: HMSO (SBL 607). 4. Miller, C. L., Miller, E. Sequeira P. J. L., Cradock-Watson, J. E., Longson, M. & Wiseberg, E. C. (1985). Effect of selective vaccination on rubella susceptibility and infection in pregnancy. British Medical Journal, 291, 1398-1401. 5. Miller, C. L., Miller, E. & Waight, P. A. (1987). Rubella susceptibility and the continuing risk of infection in pregnancy. British Medical Journal, 294, 1277-1278. 6. Miller, C. L. & Miller, C. (1985). Rubella vaccination in the UK: Time for a complete strategy. Lancet, ii, 732. 7. Miller, E., Cradock-Watson J. E. & Pollock, T. M. (1982). Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet, ii, 781-784. 8. Department of Health and Social Security. (1984). Measles Immunisation. London: DHSS, Health Notice HN(84)19, HN(FP)(84)23. 9. Christenson, B., Bottiger, M. & Heller, L. (1983). Mass vaccination programme aimed at eradicating measles, mumps and rubella in Sweden: first experience. British Medical Journal, 287, 389-391. 10. Miller, C. L., Miller, E., Begg, N. T., Morgan-Capner, P. (1987). Rubella vaccination policy: a note of reassurance. Lancet, ii, 210. 11. Anderson, R. M. & Grenfell, B. T. (1985). Control of congenital rubella syndrome by mass vaccination. Lancet, ii, 827. 12. Robbins, K. B., Branding Bennett, A. D. & Hinman, A. R. (1981). Low incidence of measles: association with enforcement of school immunisation laws. American Journal of Public Health, 71,270-274. 13. Walker, D., Carter, H. & Jones, I. (1986). Measles, mumps and rubella: the need for a change of policy. British Medical Journal, 292, 1501-1502. 14. Gill, O. N. & Begg, N. T. (1987). Public Health Laboratory Service, Communicable Disease Surveillance Centre, Communicable Disease Report 87/12, 3 4 . 15. Noah, N. D. & Urquhart, A. M. (1980). Virus meningitis and encephalitis in 1979. Journal of Infection, 2, 379-383. 16. Anderson, R. M. & May, R. M. (1983). Two-stage vaccination programme against rubella. Lancet, ii, 14161417.