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Background: Control efforts for measles and rubella are intensifying globally. It becomes increasingly important to identify and reach remaining susceptible populations as elimination is approached., Methods: Serological surveys for measles and rubella can potentially measure susceptibility directly, but their use remains rare. In this study, using simulations, we outline key subtleties in interpretation associated with the dynamic context of age-specific immunity, highlighting how the patterns of immunity predicted from disease surveillance and vaccination coverage data may be misleading., Results: High-quality representative serosurveys could provide a more accurate assessment of immunity if challenges of conducting, analyzing, and interpreting them are overcome. We frame the core disease control and elimination questions that could be addressed by improved serological tools, discussing challenges and suggesting approaches to increase the feasibility and sustainability of the tool., Conclusions: Accounting for the dynamical context, serosurveys could play a key role in efforts to achieve and sustain elimination.

There are no large-scale data on the long-term persistence of measles antibody after vaccination by the aerosol route. We therefore followed-up South African schoolchildren 6 years after their re-vaccination with Edmonston-Zagreb (EZ) and Schwarz (SW) measles vaccine given by aerosol and subcutaneous routes. Measles antibody levels and the proportion of children who were seropositive at year 6 remained significantly higher in the Edmonston-Zagreb aerosol group compared to the groups that received Schwarz or Edmonston-Zagreb vaccine subcutaneously. Measles re-vaccination by aerosol evokes a stronger and much longer lasting antibody response than injected vaccine and should thus provide more durable protection against measles.

Twenty-eight outbreaks in six regions and two major cities in Ethiopia from 2000 to 2004 were investigated, with the collection of 207 venous blood and/or oral fluid samples. Measles diagnosis was confirmed by detection of measles-specific IgM and/or detection of measles virus by polymerase chain reaction (PCR). Of 176 suspected cases tested for specific measles IgM, 142 (81%) were IgM positive. Suspected cases in vaccinated children were much less likely to be laboratory confirmed than in unvaccinated children (42% vs. 83%, P < 0.0001). Of 197 samples analyzed by RT-PCR measles virus genome was detected in 84 (43%). A total of 58 wild-type measles viruses were characterized by nucleic acid sequence analysis of the nucleoprotein (N) and hemagglutinin (H) genes. Two recognized genotypes (D4 and B3) were identified. Each outbreak comprised only a single genotype and outbreaks of each genotype tended to occur in distinct geographical locations. B3 was first observed in 2002, and has now been the cause of three documented outbreaks near to the border of Sudan. D4 genotype was previously observed in an outbreak in 1999 and occurs in more diverse locations throughout the country. These data yield insights into geographical and age-related sources of continued transmission. Refinement of measles control measures might include targeting older age groups (5-14 years) and strengthening routine immunization particularly where importation of cases is a concern., ((c) 2006 Wiley-Liss, Inc.)

Maternal and cord sera (231 pairs) were tested to measure rubella IgG levels, using a commercial immunoassay method with final fluorescent detection (ELFA). One hundred and twenty-two women had been vaccinated against rubella. Geometric mean concentrations (GMC) were not associated with time since vaccination. GMC of rubella IgG among vaccinated and unvaccinated mothers were respectively 66.6 and 80.9IU/ml (p=0.29). The corresponding values for cord sera GMC were 140.6 and 140.2IU/ml (p=0.99). These GMC values seem to have been influenced by increased transplacental transport efficiency (TTE) among vaccinated mothers. This was observed if TTE was measured as difference or ratio of cord-maternal concentration of rubella IgG, but was only statistically significantly (p=0.02) for ratio. TTE also seemed to be higher when antibody levels in mothers were below <15IU/ml. There seemed to be some interaction between susceptibility and vaccination status, but these results should be seen with caution. We do not know of a proven biological reason to support differential TTE in vaccinated and unvaccinated mothers. The sensitivity of the lab assay might have influenced the results, such that very low antibody levels in some vaccinated mothers were underestimates of true concentrations. Our finding that 38 mothers had antibody levels considered to be below the threshold for protection highlights the importance of implementing policies to vaccinate susceptible women of childbearing age.

Objective: To assess the suitability of using oral-fluid samples for determining the prevalence of immunity to vaccine-preventable infections., Methods: Paired blood and oral-fluid samples were obtained from 853 individuals of all ages from a rural Ethiopian community. Oral fluid around the gums was screened for measles- and rubella-specific antibodies using enhanced IgG antibody capture (GAC) enzyme-linked immunosorbent assays (ELISAs), and for anti-HBc antibodies using a prototype GACELISA. IgG antibodies in serum to measles, rubella and HBc were determined using commercial ELISAs., Findings: Relative to serum, oral fluid assay sensitivity and specificity were as follows: 98% and 87% for measles, 79% and 90% for rubella, and 43% and 87% for anti-HBc. These assay characteristics yielded population prevalence estimates from oral fluid with a precision equal to that of serum for measles (all ages) and rubella (ages < 20 years)., Conclusion: Our results suggest that oral fluid could have the potential to replace serum in IgG antibody prevalence surveys. Further progress requires assessment of variation in assay performance between populations as well as the availability of standardized, easy to use assays.

An IgG antibody capture enzyme linked immunosorbent assay (GACELISA) for the detection of measles specific IgG in oral fluid was developed using an FITC/anti-FITC amplification system. The GACELISA was evaluated by testing paired oral fluid and serum samples from 787 subjects in an epidemiological study of measles in rural Ethiopia. Oral fluids were tested by GACELISA and corresponding serum samples by a sensitive indirect ELISA for measles IgG (Behring Enzygnost). By comparison with the serum measles IgG assay, the oral fluid GACELISA had a sensitivity of 97.4% (95% confidence intervals: 95.9, 98.2) and a specificity of 90.0% (81.9, 94.3), with no significant differences observed by age group. Total IgG concentrations were measured on a subset of 160 oral fluids by an in-house ELISA. This showed that false negative GACELISA results tended to occur in samples with low concentrations of total IgG, although the trend was not statistically significant. It is concluded that the overall performance of the GACELISA was satisfactory, showing close agreement to the serum ELISA, and has potential to serve as an easily transferable tool for large scale epidemiological studies as required for the World Health Organisation's programme for the global control of measles.

This study was conducted to evaluate factors affecting the levels of total IgG (tIgG) and measles specific IgG (mIgG) in mother and cord sera, and the efficiency of transplacental transport of tIgG and mIgG. The study was conducted in four hospitals in Oporto, Portugal, where 1539 women and their newborns were enrolled. Measles IgG levels were lower among vaccinated mothers and respective cord sera than among vaccinated counterparts. Cord mIgG was strongly correlated with maternal levels in both vaccinated and unvaccinated groups. Transplacental transport efficiency (TTE) of mIgG decreased with increasing maternal levels, although almost one third of the observed effect was due to measurement error. The TTE was not affected by vaccination status. Monitoring maternal measles antibody levels and maternal vaccination status could be useful to determine when the age for measles vaccination can be reduced.

We analyzed data from a randomized trial of AIK-C, high-titre (EZ-H) or medium-titre EZ (EZ-M) vaccines in 3.5 and 6 month old infants in Kinshasa, Zaire, in which the occurrence of rhinorrhoea, cough, diarrhoea, fever, conjunctivitis or rash was monitored for 15 days post-vaccination (including the day of vaccination, day 0). We compared sero-response at 6 weeks and 6 months post-vaccination among children with and without mild illness at or after vaccination. Seroresponse tended to be higher in children with mild illness after vaccination than those without, whether days 0-7 or 8-15 were examined. For most symptoms, these differences did not reach statistical significance after adjusting for prevaccination maternal antibody level. However, in the EZ-M group, the proportion of children attaining at least the median post-vaccination antibody level was significantly higher in children with rhinorrhoea in days 0-7 post-vaccination than those without (adjusted odds ratio 2.6, 95% CI 1.08-6.27), as was that among children with at least one symptom in days 0-7 compared with children with no symptoms (adjusted OR 4.55, 95% CI 1.18-17.57). There were no significant differences in post-vaccination antibody levels among children with symptoms compared either to those without the specific symptom or those with no symptoms. Fever on the day of vaccination or at home visits on 7, 10 or 14 days post-vaccination, did not affect seroconversion or GMTs. Regression models showed no relation between the cumulative number of days with symptoms and antibody increase after vaccination. Analysis of antibody levels at 6 months post-vaccination showed no consistent differences according to presence or absence of symptoms. These findings provide further strong support to recommendations that mild illness is not a reason to delay measles vaccination.

We compared 3 different oral-fluid collection devices to assess their suitability for use in community studies of rubella antibody. Of 58 individuals enrolled from 13 households from a southern Ethiopian village, 38 provided a blood sample and oral fluids by the 3 devices: 2 proprietary, Omni-SAL and OraSure, and a third a polystyrene sponge swab (Sponge). The Sponge swab, used like a toothbrush, was most acceptable to survey staff and to participants of all ages, although it proved ill-adapted for fluid extraction. The other devices more often caused participant discomfort or anxiety, particularly in the young. Statistical comparison of rubella-specific immunoglobulin (Ig) G in oral fluid, measured by antibody-capture radioimmunoassay, and in serum, by indirect enzyme-linked immunosorbent assay, showed no clear differences between the devices in oral-fluid performance. Specificity range was 75-100% and sensitivity 73-85%, relative to serum. Specific-antibody levels declined with increasing age, with concomitant decreases in sensitivity, as previously documented. The relationship between specific IgG and total IgG in oral fluid differed by device. Specific IgG levels were highly correlated between paired samples using the Sponge device. We consider the Sponge device to be the most suitable for community survey work, although the extraction method requires improvement. Further work is needed to improve the sensitivity of antibody status determination in adults.

Objective: To assess the utility of oral fluid compared with serum for the determination of age-prevalence of rubella-specific antibodies in an urban African community setting., Method: Paired serum and oral fluid samples were collected from 439 individuals aged 0-49 years in Addis Ababa, Ethiopia, as part of a larger seroepidemiological survey in 1994. Oral fluid was sampled using a simple sponge device that was well accepted by subjects of all ages; venous blood was collected by Vacutainer system. We measured rubella-specific antibodies in serum by the Radial Haemolysis (RH) test, supported by two confirmatory assays, and in oral fluid by IgG antibody-capture radioimmunoassay (GACRIA)., Results: Sensitivity and specificity of oral fluid results compared to serum were 89% and 76%, respectively. Sensitivity declined from 96% in age group 0-19 years to 90% in age group 20-29 and 78% in age group 30-49. Specificity was 86% in 0-9 year olds contrasting with 61% in older groups (10-49 years). The positive predictive value of an oral fluid sample was high in all age groups (range 92-100%), while the negative predictive value declined from > or =80% in those aged <10 years to <10% in those aged > or =30 years. Serum confirmatory tests suggested a proportion of false serum RH negatives, increasing with age, indicating a need to standardize serum as well as oral fluid tests., Conclusion: In the community setting of a developing country, oral fluid surveys could be useful to estimate age-prevalence of rubella immunity and identify rubella-susceptible children for follow-up. Further work is required to simplify assays and sample processing, improve assay sensitivity and estimate assay specificity more precisely, and compare and standardise collection methods suitable for surveillance of a variety of childhood viral infections.

The response to measles revaccination was evaluated in 1994 among 202 Bolivian school-aged children whose antibody levels were below 200 miu (milli-international units) by haemagglutination inhibition (HI) in a large-scale serosurvey conducted in Santa Cruz one year earlier. Of the 202 revaccinated children, 164 (82%) had seroconverted between the 1993 serosurvey and the pre-revaccination blood sample. A measles outbreak occurred in Santa Cruz 6 months before the revaccination. Among the seroconvertors, only 6% gave a history of measles, and 15% a history of contact with a case of measles. All 20 children with undetectable HI antibody pre-revaccination, and all 6 children with levels below 100 miu, seroconverted after revaccination. The geometric mean titres by HI at 4 weeks after revaccination were 2018 miu (95% confidence limits [95% CL] 1143, 3564) and 398 miu (95% CL 254, 625) in the 2 groups, respectively. Six of 9 children with pre-revaccination antibody titres of 100-199 miu also seroconverted. No child demonstrated a measles-specific immunoglobulin M response. Among the 29 children who seroconverted and were followed up at one year after revaccination, 15(52%) showed a fourfold or greater decline in antibody levels, which in 8 fell to levels below 200 miu. This study confirmed the observation that revaccination is successful in producing an antibody response in children with low or undetectable pre-revaccination titres, but it also confirmed that vaccine-induced immunity wanes rapidly.

Where immunization campaigns locally eliminate measles, it will be important to identify the vaccination policy most likely to prevent future epidemics. The optimum age for vaccination depends on the rate of decline of maternal antibody, because the presence of antibody reduces vaccine efficacy. The first part of this paper contains a quantitative reappraisal of the data on antibody decline and seroconversion rates by age. The decline in maternal antibody protection follows delayed exponentials, with delays of 2-4 months, and subsequent half-lives of 1-2 months. Using this result in an analytical mathematical model we find that the optimal age to administer a single dose of vaccine to children, which is independent of vaccine coverage, lies within the range 11-19 months. We also show that, where the optimal age cannot be met, it is better to err towards late rather than early vaccination. There are therefore two reasons why developing countries, which presently vaccinate during infancy because measles transmission rates are high should eventually switch to the second year of life. The possible gains from two-dose vaccination schedules are explored with respect to both coverage and efficacy. A two-dose schedule will be beneficial, in principle, only when there is a need to increase net vaccine efficacy, after coverage has been maximized with a one-dose schedule.

We conducted a community-based survey in Santa Cruz city, Bolivia, to determine the age-specific prevalence of measles antibodies, determine factors associated with absence of detectable measles antibodies, and to compare results of salivary and serum measles immunoglobulin G (IgG) antibody assays. Serum samples from 1654 children were assayed for measles IgG antibody using the haemagglutination inhibition (HI) assay, and salivary samples were also obtained from 187 children and tested for measles IgG antibody using an antibody capture radioimmunoassay. Reported measles vaccine coverage in children aged 12-35 months was 77% (95% confidence interval [CI], 72-81%). Eighty-seven percent (95% CI 85-89%) had detectable HI antibody, but a high proportion had antibody levels below 200 miu (30-40% of 2-14 years old children). Measles seronegativity was associated with not being vaccinated against measles, a negative history of measles disease, living in the inner city, being a lifetime resident of Santa Cruz, and young age. Of 212 children without detectable measles antibody, 58% had a positive history of vaccination or measles disease, so that historical information was not sufficiently reliable to identify susceptibles. The salivary measles antibody assay was not sufficiently sensitive to be used for population screening; only 54% of 171 salivary samples from children who had detectable serum HI antibody were positive. A mass measles vaccination campaign of all children under 15 years of age is planned in Bolivia in 1994. Although only 7% of school-age children in Santa Cruz were seronegative, the effectiveness of a mass campaign in this age group depends in part on the response to revaccination of children with low, but detectable, antibody levels.