Balancing Evidence and Uncertainty when Considering Rubella Vaccine Introduction

Background

Despite a safe and effective vaccine, rubella vaccination programs with inadequate coverage can raise the average age of rubella infection; thereby increasing rubella cases among pregnant women and the resulting congenital rubella syndrome (CRS) in their newborns. The vaccination coverage necessary to reduce CRS depends on the birthrate in a country and the reproductive number, R₀, a measure of how efficiently a disease transmits. While the birthrate within a country can be known with some accuracy, R₀ varies between settings and can be difficult to measure. Here we aim to provide guidance on the safe introduction of rubella vaccine into countries in the face of substantial uncertainty in R₀.

Methods

We estimated the distribution of R₀ in African countries based on the age distribution of rubella infection using Bayesian hierarchical models. We developed an age specific model of rubella transmission to predict the level of R₀ that would result in an increase in CRS burden for specific birth rates and coverage levels. Combining these results, we summarize the safety of introducing rubella vaccine across demographic and coverage contexts.

Findings

The median R₀ of rubella in the African region is 5.2, with 90% of countries expected to have an R₀ between 4.0 and 6.7. Overall, we predict that countries maintaining routine vaccination coverage of 80% or higher are can be confident in seeing a reduction in CRS over a 30 year time horizon.

Conclusions

Under realistic assumptions about human contact, our results suggest that even in low birth rate settings high vaccine coverage must be maintained to avoid an increase in CRS. These results lend further support to the WHO recommendation that countries reach 80% coverage for measles vaccine before introducing rubella vaccination, and highlight the importance of maintaining high levels of vaccination coverage once the vaccine is introduced.     

Rubella antibody titres and immunization status in a family practice.

Rubella vaccination status and immunity to rubella were studied in 230 "active patients" aged 8 to 22 years in a teaching family practice by means of a chart review and measurement of the rubella antibody titre in a blood sample. Of the 200 patients who submitted a blood sample 161 (80%) were found to be immune, having a rubella hemagglutination-inhibiting antibody titre of 1:16 or greater. Log linear analysis showed that immunity to rubella was independent of a history of rubella, and that 94% of the vaccinated patients versus 74% of the unvaccinated patients (a significant difference; P = 0.007) were immune. In retrospect we estimated that 80% of the study group were protected at the start of the study. After surveillance and follow-up, with vaccination of 27 of the 39 patients identified as susceptible to rubella, this estimated proportion increased to 90%. The study showed that there is nothing to be gained by asking about a history of rubella but that vaccination against this disease is increasing among children aged 5 to 9 years.     

A Socio-Demographic Examination of Adults Responding to Governmental Vaccination Recommendations during the Japanese Rubella Outbreak of 2013

Background

In 2013 a rubella outbreak occurred among Japanese people of working-age which resulted in 14,357 reported cases. The Japanese government subsequently recommended voluntary vaccination or rubella antibody testing for young women (15–49 years of age) who were planning to conceive and for adult men, children, and other persons in potential contact with pregnant women at home. However, the expense and time involved for vaccination, antibody testing and visiting a clinic may represent a major barrier to voluntary compliance among this busy demographic. The aim of the current study was, therefore, to examine potential relationships between the social background of Japanese working-age individuals affected by the 2013 voluntary vaccination campaign.

Methods

A web-based survey of 1,889 Japanese men and women aged 20–49 years was conducted in early 2014. Statistical analyses were used to explore the associations between social background and testing for rubella antibody and / or vaccination uptake during the previous year.

Results

Twenty-four percent of respondents who were planning a pregnancy had been tested for rubella antibody or vaccinated in 2013. However, among those without a current desire for pregnancy, 3% of men and 7% of women, respectively, were tested or vaccinated. Regardless of whether they were planning to conceive, testing for rubella antibodies or vaccination was statistically associated with having acquaintances who had been vaccinated, understanding the government recommendations, and being able to confirm their lack of rubella vaccination history using Maternal and Child Health Handbook records in both men and women.

Conclusion

To help eliminate rubella in Japan, additional initiatives need to target Japanese individuals who cannot envisage a direct benefit from vaccination. The results of this study suggest that disseminating the government recommendation to all potentially affected subpopulations, along with maintaining life-time vaccination records might offer a solution to encourage vaccination uptake among working-age adults in Japan, as elsewhere.     

Evaluation of rubella screening in pregnant women

BACKGROUND: The rationale for rubella vaccination in the general population and for screening for rubella in pregnant women is the prevention of congenital rubella syndrome. The objective of this study was to evaluate the effectiveness of the prenatal rubella screening program in Quebec. METHODS: A historical cross-sectional study was designed. Sixteen hospitals with obstetric services were randomly selected, 8 from among the 35 "large" hospitals in the province (500 or more live births/year) and 8 from among the 50 "small" hospitals (fewer than 500 live births/year). A total of 2551 women were randomly selected from all mothers of infants born between Apr. 1, 1993, and Mar. 31, 1994, by means of stratified 2-stage sampling. The proportions of women screened and vaccinated were ascertained from information obtained from the hospital chart, the physician''s office and the patient. RESULTS: The overall (adjusted) screening rate was 94.0%. The rates were significantly different between large and small hospitals (94.4% v. 89.6%). Five large hospitals and one small hospital had rates above 95.0%. The likelihood of not having been screened was statistically significantly higher for women who had been pregnant previously than for women pregnant for the first time (4.8% v. 1.4%; p < 0.001). Of the 200 women who were seronegative at the time of screening (8.4%), 79 had been vaccinated postpartum, had a positive serological result on subsequent testing or did not require vaccination, and 59 had not been vaccinated postpartum; for 62, subsequent vaccination status was unknown. INTERPRETATION: Continued improvement in screening practices is needed, especially in small hospitals. Because vaccination rates are unacceptably low, it is crucial that steps be taken to address this issue.     

Absence of cell-mediated immunity to rubella virus 5 years after rubella vaccination.

The long-term effectiveness of rubella vaccination in childhood is particularly important because the ultimate goal of immunization is the prevention of infection during pregnancy. Of 25 healthy children tested 4 to 5 years after rubella vaccination, 19 showed no evidence of cell-mediated immunity (CM) to rubella virus despite the presence of hemagglutination-inhibition or complement-fixation antibodies or both. Twenty-two of 25 seropositive, naturally infected young adults showed evidence of CMI. These results indicate that fetuses of women who have been vaccinated against rubella may not be protected against damage by wild rubella infection during the pregnancy, when CMI is physiologically depressed.     

Vaccination against human papillomavirus in childhood: the next rubella analogue?

Direct comparisons between different vaccination programmes can reveal new targets and solve challenges that have been faced and managed in the past during similar health interventions. In the rubella vaccination programme both boys and girls were included in order to ensure that women of childbearing age are effectively protected. For human papillomavirus (HPV) vaccination, at the moment only girls have been included into the scheme. The aspect of vaccinating both boys and girls against HPV, similarly to the rubella paradigm, would interrupt "high-risk" HPVs transmission from males to females and vice versa ensuring further elimination of HPV. The new generation of HPV vaccines is expected to cost less and this will contribute to the possible introduction of HPV vaccine in both males and females.     

Simulations of rubella vaccination strategies in China

Many infants whose mothers have rubella infections during their first trimester of pregnancy have birth defects called congenital rubella syndrome (CRS). China does not routinely vaccinate against rubella in the public sector, but may need to start as its 'one child per couple' policy changes the population age distribution and the dynamics of rubella epidemiology, so that the incidence of rubella in pregnant women increases. Computer simulations with demographic transitions and rubella transmission dynamics predict that, with no or limited rubella vaccination, CRS incidence in China in the 30 years after 2020 will be more than twice the level in 2005. Comparisons of rubella vaccination strategies using computer simulations show that routine vaccination of over 80% of 1-year-old children would be effective in reducing total CRS cases in 2005-2051 and eliminating rubella in China by 2051. Routine immunizations at higher levels and the addition of early mass vaccinations of 2-14-year-old children and women of childbearing ages would further reduce total CRS cases and speed up the elimination of rubella.     

Effect of selective vaccination on rubella susceptibility and infection in pregnancy.

The effect of school and adult vaccination on susceptibility to rubella in women of childbearing age was assessed in the Manchester area, where the population attending antenatal clinics is over 40 000 a year. Between 1979 and 1984 the proportion susceptible fell from 6.4% to 2.7%. In 1984, 4.2% of nulliparous women were susceptible compared with 1.4% of women in their second or subsequent pregnancy. Eighty five per cent of pregnant women screened and found to be non-immune were vaccinated post partum before leaving hospital. Requests for prevaccination screening of non-pregnant women increased in response to a national campaign and at the time of local outbreaks of rubella but only two thirds of those found to be nonimmune were subsequently vaccinated. During 1983 and 1984 infection was confirmed in 57 pregnant women--2% of those non-immune. Selective vaccination has reduced susceptibility to rubella in the childbearing population, but it is suggested that mass vaccination of children of both sexes should be added to the existing policy to control circulation of wild rubella virus and reduce the risk of infection to pregnant women who remain susceptible.     

Rubella: immunity and vaccination in schoolgirls.

Of 191 schoolgirls, 128 volunteered to take part in a feasibility study of serotesting before and after rubella vaccination, and all responded to RA 27/3 vaccine. Had the serum samples been taken by a fingerprick method the number of volunteers would probably have increased considerably. A change in policy for rubella vaccination to testing both before and after vaccination would cost no more than the existing policy, would ensure primary response, and would differentiate those women who were protected by the vaccine from those with antibody to wild virus.     

Can we prevent an increase in the incidence of congenital rubella syndrome in the next decade?

The immunity to rubella of 115 girls aged 10 to 14 years was tested in 1978. The proportion of girls found to be immune was 80%, similar to rates in the prevaccination era. Nearly half of the immunity was from documented vaccination, and the other half was presumably from infection with wild rubella virus. The vaccination failure rate was 12%. Because of declining immunity to rubella of women of child-bearing age, detecting low levels of immunity in these women is becoming increasingly important. Immunization of 12- to 15-month-old children has not been effective. Vaccinating all girls 10 to 12 years old would likely be the most effective method of preventing an increase in the incidence of congenital rubella syndrome in the next decade.     

Rubella immunity in pregnant women in a north London practice.

Congenital malformations due to rubella embryopathy are preventable. All women embarking on pregnancy should be immune and know that they are immune to rubella to guard against the risk of contracting the disease during pregnancy. A previous history of clinical rubella or rubella vaccination is not reliable, and women should be screened for antibodies when possible before planning to conceive, and particularly before a first pregnancy. As general practitioners committed to the practice of prevention, we should undertake rubella screening for all our women patients before they conceive. This could easily be incorporated into our contraceptive services. We will be greatly helped if family planning clinics adopted a policy of screening for rubella antibodies, always remembering that good documentation and communication will avoid duplication and confusion and reduce costs.     

Seroprevalence of measles-, mumps- and rubella-specific IgG antibodies in german children and adolescents and predictors for seronegativity

We have undertaken a seroprevalence study with more than 13,000 children, who had been included in the German KIGGS survey, a representative sample of children and adolescents 0-17 years of age. The IgG titres against measles, mumps and rubella were determined in 1 to 17 year olds While 88.8% of the children were MMR-vaccinated at least once, 76.8% of children aged 1 to 17 years showed prevalence of antibodies to MMR. The highest seronegativity was seen with respect to mumps. Gender differences were most pronounced with regard to rubella IgG titres: girls aged 14 to 17 years were best protected, although seronegativity in 6.8% of this vulnerable group still shows the need of improvement. Search for predictors of missing seroprevalence identified young age to be the most important predictor. Children living in the former West and children born outside of Germany had a higher risk of lacking protection against measles and rubella, while children with a migration background but born in Germany were less often seronegative to measles antibodies than their German contemporaries. An association of seronegativity and early vaccination was seen for measles but not for mumps and rubella. A high maternal educational level was associated with seronegativity to measles and rubella. In vaccinated children, seronegativity was highest for mumps and lowest for rubella. For mumps, high differences were observed for seronegativity after one-dose and two-dose vaccination, respectively. Seronegativity increases as time since last vaccination passes thus indicating significant waning effects for all three components of MMR.     

Rubella in teenagers: epidemiology and prophylaxis in Siena, Italy

Six hundred and fifty-three teenagers (aged 11-13 year) living in Siena and its surroundings (Tuscany, Italy) were the sample for serological screening intended to ascertain immunity to rubella. It was found that 324 of the teenagers (49.62%) lacked antibodies and, hence, were unprotected against the infection. Out of the 324 girls, 196 (around 3/5) were vaccinated using live vaccine. Post-vaccinal complications, with clinical signs of rubella infection, were recorded in almost one third of the vaccinees. Virus isolation from the blood was, in every case, not possible after either 10 or 30 days from vaccination. The serological findings, expressed in hemagglutination inhibition antibodies, could be summarized in the following way: (i) antibodies at low titre were found in only eight out of 184 girls (4.35%) ten days after vaccination; (ii) serological conversion was recorded in 187 out of 188 girls (99.47%) 30 days after vaccination; (iii) the titres were moderately high but much lower than those recorded for the natural infection. The results are discussed in the context of their implications for the strategies of rubella vaccination as far as the safety and the effectiveness of the vaccine are concerned, with emphasis on the duration of the protective immunity.     

Increase in congenital rubella occurrence after immunisation in Greece: retrospective survey and systematic review

ObjectiveTo describe the events leading to the epidemic of congenital rubella syndrome in Greece in 1993 after a major rubella epidemic.DesignRetrospective survey and systematic review.SettingGreece (population 10 million), 1950-95.SubjectsChildren, adolescents, and women of childbearing age.ResultsAround 1975 in Greece the measles, mumps, and rubella vaccine started being given to boys and girls aged 1 year without policies to attain high vaccination coverage and to protect adolescents and young women. During the 1980s, vaccination coverage for rubella remained consistently below 50%, and the proportion of pregnant women susceptible to rubella gradually increased. In 1993 the incidence of rubella in young adults was higher than in any previous epidemic year. The epidemic of congenital rubella that followed, with 25 serologically confirmed cases (24.6 per 100 000 live births), was probably the largest such epidemic in Greece after 1950.ConclusionsWith low vaccination coverage, the immunisation of boys and girls aged 1 year against rubella carries the theoretical risk of increasing the occurrence of congenital rubella. This phenomenon, which has not been previously reported, occurred in Greece.     

Vaccination against measles, mumps and rubella (MMR): a comparison between the antibody responses at the ages of 18 months and 12 years and between different methods of antibody titration

In connection with the introduction of the trivalent vaccine against measles, mumps and rubella at 18 months and 12 years of age, an evaluation of the seroconversion and booster effects in the two age-groups was carried out. This also comprised different laboratory-test methods appropriate for follow-up studies after large-scale, vaccination studies. The measles, mumps and rubella antibodies were measured by the haemolysis-in-gel (HIG) method. Measles antibodies were also measured by the haemagglutination-inhibition (HI) test. Borderline values or samples negative to measles or mumps were also tested by the serum-neutralization (SN) test. All but four of 150 18-month-old children lacked antibodies against measles by the HI test and one of these by the HIG method. Against mumps, 99% were seronegative in the HIG test and 97% in the SN test and two against rubella prior to vaccination. Among 247 schoolchildren, 60 (24%) lacked antibodies in the HI test and 28 (11%) of these also in the HIG test. Sixty-six schoolchildren (25%) were negative to mumps and 45% to rubella prior to vaccination. The seroconversion rate for the 18-month-old children was 96% against measles, 93% against mumps and 99% against rubella. The figure for the schoolchildren was 82% against measles, 80% against mumps and 100% against rubella. On comparing the titre levels in seroconverting children, the measles-antibody levels were found to be lower among older children, compared with younger, while the opposite was true for rubella.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of rubella vaccination programme in schools on rubella immunity in a general practice population.

Between November 1979 and January 1980 all patients aged 13-21 years who attended a general practice in Glasgow were tested for their immunity against rubella (single radial haemolysis test). All of the women in the sample should have been vaccinated at 13 as part of the rubella vaccination programme, which began in Glasgow in 1971. The programme excludes boys. Of the 77 females and 64 male patients studied, nine (11.7%) and 10 (15.6%), respectively, were susceptible to the infection. For only 34 women was evidence of vaccination documented in the practice records, and three of those either had failed to seroconvert or had antibody below detectable values. Overall there was no significant differences between the proportion of men and women who were susceptible to the disease. The rubella vaccination programme had clearly failed to reduce the number of susceptible women in this practice. Hence the immune state of all girls should be checked at about 15 years of age, so that as many as possible may be rendered immune before they leave school.     

Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination

Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single-dose seroconversion rates ~95 %. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects aged 11–22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (age 18–40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination.     

Rubella in Russia: variability of the infectious agent during the period of vaccine prophylaxis

AIM: To assess influence of vaccination against rubella on the genetic diversity of rubella virus. MATERIALS AND METHODS: Vaccine strains of rubella virus Wistar 27/3 and Orlov-B as well as sera from patients with rubella obtained in Perm region during 1999 - 2005 period and standard serologic, molecular, epidemiologic and statistical methods were used. The study was performed according to the WHO recommendations on the genotyping of wild rubellavirus strains. RESULTS: Strains of rubella virus isolated in Perm region, vaccine strain Orlov-B (Saint Petersburg), and 4 Russian strains isolated in 1967-1997 before vaccine introduction belong to the same genetic group with high degree of homology - genetic divergence do not exceed 0 - 1%. This group was identified as genotype 2c which, according to WHO's data, circulates only in Russia. Periods of epidemic peaks of rubella incidence and its falls as well as selective immunization of girls and women of childbearing age did not influence on the genetic stability of the virus (divergence did not exceed 0.6 - 2.0%). On the contrary, mass immunization of children aged 1 - 2 years during 4 years resulted in statistically significant changes of rubella virus subtype inside the genotype 2c. CONCLUSION: Ten-year experience of rubella vaccination in Perm region demonstrates necessity of inclusion of monitoring for rubella virus variability in the system of epidemiological surveillance and control for rubella infection during period of its prevention by vaccine.     

Serologic Vaccination Response after Solid Organ Transplantation: A Systematic Review

Background

Infectious diseases after solid organ transplantation (SOT) are one of the major complications in transplantation medicine. Vaccination-based prevention is desirable, but data on the response to active vaccination after SOT are conflicting.

Methods

In this systematic review, we identify the serologic response rate of SOT recipients to post-transplantation vaccination against tetanus, diphtheria, polio, hepatitis A and B, influenza, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides, tick-borne encephalitis, rabies, varicella, mumps, measles, and rubella.

Results

Of the 2478 papers initially identified, 72 were included in the final review. The most important findings are that (1) most clinical trials conducted and published over more than 30 years have all been small and highly heterogeneous regarding trial design, patient cohorts selected, patient inclusion criteria, dosing and vaccination schemes, follow up periods and outcomes assessed, (2) the individual vaccines investigated have been studied predominately only in one group of SOT recipients, i.e. tetanus, diphtheria and polio in RTX recipients, hepatitis A exclusively in adult LTX recipients and mumps, measles and rubella in paediatric LTX recipients, (3) SOT recipients mount an immune response which is for most vaccines lower than in healthy controls. The degree to which this response is impaired varies with the type of vaccine, age and organ transplanted and (4) for some vaccines antibodies decline rapidly.

Conclusion

Vaccine-based prevention of infectious diseases is far from satisfactory in SOT recipients. Despite the large number of vaccination studies preformed over the past decades, knowledge on vaccination response is still limited. Even though the protection, which can be achieved in SOT recipients through vaccination, appears encouraging on the basis of available data, current vaccination guidelines and recommendations for post-SOT recipients remain poorly supported by evidence. There is an urgent need to conduct appropriately powered vaccination trials in well-defined SOT recipient cohorts.