Successful Elimination of Endemic Rubella in the WHO European Region. Is It Proper to Remove the Recommendation for Preconceptional Immunization?

BACKGROUND: Rubella is a contagious viral infection that has garnered significant attention in the field of public health due to its potential consequences, especially during pregnancy. In recent decades, it has been recommended that non-immune women receive immunization during the preconceptional and/or postpartum periods. The goal of this strategy is to prevent primary rubella infection in order to protect pregnant women against congenital rubella syndrome. In November 2022, the WHO's Regional Verification Commission declared the elimination of rubella infection in Italy. In recent years, the main migration flows to Italy have originated from regions where rubella has not yet been eliminated and where no program is in place to achieve this goal. OBJECTIVE: The aim of this study was to retrospectively assess rubella immunity in pregnant women who have attended three delivery centers in Rome over the past three years, from January 2021 to May 2023. METHODS: Data about the rubella serological status of 7937 non-consecutive pregnant women were collected. Univariate analysis was performed to verify any difference between the study groups in terms of age distribution. RESULTS: Anti-rubella IgG antibodies were found in 7224 (91%) women while 713 (9%) were susceptible to rubella (IgG negative), without differences in terms of immunity rate between Italian and non-Italian women. Age analysis showed a statistically significant older age of immune women than receptive women and of Italian immune women than non-Italian immune women. CONCLUSIONS: The National Plan for the Elimination of Measles and Congenital Rubella aimed to achieve a percentage of susceptible women of childbearing age below 5%. These data indicate the relevance of maintaining the recommendation for preconceptional rubella vaccination in Italy.

Routine Childhood Vaccines Given From 1 through 18 Years of Age.

In addition to the vaccines due in the first year of life, the US Advisory Committee on Immunization Practices recommends that children continue to receive vaccines regularly against a variety of infectious diseases. Starting at 12 to 15 months of life, these include the two-dose measles-mumps-rubella vaccine series and the two-dose varicella vaccine series. Also in the second year of life, infants should begin the two-dose hepatitis A vaccine series and complete the Haemophilus influenzae type B vaccine series as well as the pneumococcal conjugate vaccine series. Before 19 months of life, infants should receive the third dose of the poliovirus vaccine and the fourth dose of diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The final doses of poliovirus and tetanus-diphtheria-acellular pertussis vaccines are both due at 4 to 6 years of life. Before each influenza season, every child should receive the influenza vaccine. Those less than 9 years of age who previously received less than two doses need two doses a month apart. At 11 to 12 years of life, all should get two doses of the human papillomavirus vaccine, the adolescent/adult version of the tetanus-diphtheria-acellular pertussis vaccine, and begin a two-dose series of meningococcal ACWY vaccine. Each of these vaccines is due when the vaccine works to protect against both an immediate risk as well as to provide long-term protection. Each vaccine-preventable disease varies in terms of the nature of exposure, the form of the morbidity, the risk of mortality, and potential to prevent or ameliorate its harm.

Standardization of rubella immunoassays.

Currently, rubella and congenital rubella has been eliminated or is becoming a rare disease in many countries that have implemented effective vaccination programs. In most of these countries, it is recommended and of major importance to screen childbearing age women in order to identify susceptible women and offer them vaccination before pregnancy or after delivery. Immunity to rubella virus (RV) is commonly determined by measuring rubella-specific IgG (RV-IgG). However, looking at literature, it is obvious that standardization of RV-IgG assays is not effective, with different levels of International Units per milliliter (IU/mL) reported for a same sample, and consequently different interpretations of the result. This situation leads to misinterpretation of results, sometimes causing adverse clinical outcomes. This article aimed to review several factors, such as the introduction of large-scale vaccination programs and changes in epidemiology of RV infection, along with the development of new technologies that have complicated appreciation of the immune status of patients. However, there is currently no evidence that these factors may be of any influence on rubella resurgence.

Immunocytochemical focus assay for potency determination of measles-mumps-rubella trivalent vaccine.

The immunocytochemically stained focus assay for the determination of potency of individual components in measles-mumps-rubella trivalent vaccine is described. The method involves the reaction of infected cultures maintained under the agar overlay medium sequentially with rabbit antiserum specific to each component, biotinylated anti-rabbit IgG serum, avidin-biotinylated-peroxidase complex, and substrate mixture. The potency of one component determined by the method was not influenced by the presence of two other components and was comparable to that determined by either dilution end point titration or plaque assay. The method offers a number of advantages over the current method based on neutralization of components other than the one to be titrated.

Improvement in potency assay of measles-mumps-rubella trivalent vaccine: interference between components and measures for its elimination.

In the potency assay of trivalent measles-mumps-rubella (MMR) vaccine by the immunocytochemical focus assay reported previously (Fukuda et al., 1987), development of rubella foci in RK13 cells was inhibited in the presence of a large excess of mumps component, resulting in an underestimation of the titre of the rubella component. When RK13 cells are infected with the mixture of mumps and rubella viruses, mumps virus interfered with the growth of rubella virus. Interference was mediated most likely by interferon induced by mumps virus. The interference was eliminated by a partial neutralization of mumps component by the addition of anti-mumps serum to the inoculum to RK13 cells. Improved method of potency assay of MMR vaccine incorporating the above measures and other modifications are described.

A simple vaccination model with multiple endemic states.

A simple two-dimensional SIS model with vaccination exhibits a backward bifurcation for some parameter values. A two-population version of the model leads to the consideration of vaccination policies in paired border towns. The results of our mathematical analysis indicate that a vaccination campaign φ meant to reduce a disease's reproduction number R(φ) below one may fail to control the disease. If the aim is to prevent an epidemic outbreak, a large initial number of infective persons can cause a high endemicity level to arise rather suddenly even if the vaccine-reduced reproduction number is below threshold. If the aim is to eradicate an already established disease, bringing the vaccine-reduced reproduction number below one may not be sufficient to do so. The complete bifurcation analysis of the model in terms of the vaccine-reduced reproduction number is given, and some extensions are considered.

Rubella--a safe and necessary vaccine.

There is no evidence at all to suggest that cendehill vaccine is even potentially carcinogenic. There is every evidence that unless pregnant women are protected against rubella, children will continue to be born with severe and preventable defects. Present vaccination policies are likely to be effective and should be pursued.

[Comparison of the efficacy of various strains of mumps vaccine: a school survey]. / Comparaison de l'efficacité de différentes souches de vaccin ourlien: une enquête en milieu scolaire.

BACKGROUND: Since the beginning of the program of immunization of children against measles, mumps and rubella (MMR) in 1987, various outbreaks of mumps have occurred in Switzerland, with a significant proportion of cases in immunized children. Previous studies have suggested a possible lack of efficacy of the Rubini vaccine strain, which has been much used in this country. METHODS: Incidence study of secondary cases of mumps in the schools of Geneva, between March 18th and June 30th 1994. STUDY POPULATION: During the study period, mumps outbreaks have been observed in 10 school classes. After exclusion of the 10 primary cases, the study population comprised 195 children aged 4 to 12 years. RESULTS: Raw estimation of vaccine efficacy against mumps was 72.5%. Whereas both the Urabe and Jeryl-Lynn strains showed a significant efficacy, the Rubini strain didn't show any significant protective effect. After adjustment by Poisson regressions for the confounding effect of age, efficacy rates and 95% confidence limits were 75.8% (35.6%, 90.9%) for Urabe; 64.7% (10.6%, 86.0%) for Jeryl-Lynn; and 12.4% (-102%, 62.1%) für Rubini. CONCLUSION: This study didn't show any protective effect of the Rubini vaccine strain. Furthermore, it demonstrated a statistically significant protective effect of the Urabe and Jeryl-Lynn strains, compared to the Rubini strains. In this conditions the use of the Rubini strain should be restricted to situations of confirmed contra-indications to the other vaccinal strains, as long as its protective efficacy is not clearly demonstrated.

[Mumps epidemiology in Switzerland: results from the Sentinella surveillance system 1986-1993. Sentinella Work Group]. / Mumps-Epidemiologie in der Schweiz: Ergebnisse der Sentinella-Uberwachung 1986-1993. Sentinella-Arbeitsgemeinschaft.

UNLABELLED: Since 1990, there have been reports of an increasing number of mumps cases in Switzerland, in particular among vaccinated children, and of local outbreaks of mumps. Using data from the Sentinella reporting system, a network of voluntary participating doctors (general practitioners, internists and paediatricians, yearly average: n = 141), trends and factors influencing mumps incidence in the general population were assessed during the last seven years. Following an initial decline in mumps reports, since 1990, there has been a continuous and marked increase in reports from a minimum of 0.7 cases per physician and year in 1989/90 to a near five-fold increase of 3.3 cases in the last reporting period from June-December 1993 (calculated for one year). Half of this increase, which is reflected in a doubling of the number of cases reported in 1986/87, is explained by an increase in cases among vaccinated children. The trend in mumps cases contrasts with that of measles and rubella, where there has been a clear decline in these reports since 1986 (approximately 70-80%). Complications were reported in 75 (4.0%) of the total number of mumps patients (n = 1894); in 2/5 of the cases this was a meningitis, in 1/3 an orchitis. Based on available data on vaccination coverage, the estimated efficacy of the mumps vaccines against parotitis is between 47-77%; this is clearly lower than the corresponding figure for measles (91-97%) and rubella (89-97%) vaccines. The relatively low efficacy against parotitis is mainly due to a protective level of 13-73% of the vaccines containing the Rubini strain. The estimated efficacy of the Rubini vaccines against complications is 50-81%; it is nearly 60-90% if a possible reporting bias is taken into consideration. CONCLUSIONS: 1. The Rubini strain vaccines, which are the most commonly used in Switzerland, seem to have played an important role in the clear increase in mumps cases since 1990. 2. The situation seems more favourable concerning the efficacy against complications of the vaccines used. 3. Our data support the high efficacy of all measles and rubella vaccines. 4. The surveillance of MMR by the Sentinella reporting system provides a useful and effective manner to evaluate the MMR vaccination programme.

Development of a high-throughput rubella virus infectivity assay based on viral activation of caspases.

Rubella virus (RV, German measles) is a teratogenic agent that can lead to serious congenital defects after maternal infection during early pregnancy. Currently, the disease can be prevented effectively by available live attenuated vaccines. An important requisite for the manufacture and release of a safe and potent live virus vaccine is the measurement of the vaccine titer (potency), to ensure the correct dose and efficacy of the vaccine. One historical method for measuring potency is the endpoint dilution TCID(50) assay. Traditionally, RV TCID(50) titers are calculated after visual inspection of cells for presence of cytopathic effect (CPE). Such visual scoring is tedious and labor intensive. The development of a new TCID(50) readout method, based on a fluorescent molecular marker of RV-induced apoptosis, is described in this report. Further, in order to calculate TCID(50) potency a novel mathematical model was established to convert the numerical fluorescence measurements into categorical data. Finally, the assay parameters such as signal-to-noise ratio, robustness, variability and bias were optimized. This new readout method demonstrated strong concordance with the standard manual scoring of CPE, and therefore can provide a practical, objective and higher-throughput alternative to the traditional TCID(50) readout used for calculating titers of rubella virus.

Effects of adverse storage on live virus vaccines.

A vaccine stored strictly according to the manufacturer's instructions can be used with confidence up to the designated expiry date. However, problems with transport, refrigeration plant, or electricity supply may lead to the exposure of a vaccine under field conditions, and particularly in tropical countries, to high or fluctuating temperatures. We have therefore studied the stability of the standard formulations of our live yellow fever virus, poliovirus and rubella virus vaccines, when they were deliberately exposed to high temperatures, or to alternating cycles of high and low temperatures, intended to simulate such conditions. Our results suggest that with these vaccines, the consequences of adverse storage are not likely to be serious.

Stability characteristics of freeze-dried human live virus vaccines.

Freeze-drying (lyophilization) of biologically active materials such as human live virus vaccines is an accepted method of preserving potency. Since freeze-drying does not assure total stability, a formal system of monitoring stability, i.e., potency, has been established. Two experimental desings are utilized: (1) Long term studies to duplicate normal use storage at -20 degrees C and 2-8 degrees C and (2) Accelerated studies which predict long term stability through regression analysis using the Arrhenius equation. Data summarizing stability experience over a long period of study will be presented.

A European collaborative study to assess the proficiency of laboratory estimates of potency of live measles, mumps and rubella tri-valent vaccines.

A collaborative study involving 10 European laboratories was undertaken to assess the variability of estimates of the potency of measles, mumps and rubella tri-valent vaccines. The precision of assays as demonstrated by tests on duplicate samples was good; differences averaged around 0.2 log10 steps. Similarly, assay to assay variation within laboratories was small with most achieving consistency around 5% over three assays. In contrast, overall median variations in potency between laboratories were around 1.0 log10 for measles, 3.0 log10 for mumps and 2.0 log10 for rubella. Unexpectedly, the variations in estimates for measles and rubella were not improved when potencies were expressed relative to reference preparations. However, for mumps variability was reduced by using a reference but only for the vaccines of the same strain as the reference. For these Urabe mumps vaccines the variation in relative potency was around 1.5 log10.