How much does it cost to measure immunity? A costing analysis of a measles and rubella serosurvey in southern Zambia.

BACKGROUND: Serosurveys are a valuable surveillance tool because they provide a more direct measure of population immunity to infectious diseases, such as measles and rubella, than vaccination coverage estimates. However, there is concern that serological surveys are costly. We adapted a framework to capture the costs associated with conducting a serosurvey in Zambia. METHODS: We costed a nested serosurvey in Southern Province, Zambia that collected dried blood spots from household residents in a post-campaign vaccine coverage survey. The financial costs were estimated using an ingredients-based costing approach. Inputs included personnel, transportation, field consumable items, social mobilization, laboratory supplies, and capital items, and were classified by serosurvey function (survey preparation, data collection, biospecimen collection, laboratory testing, and coordination). Inputs were stratified by whether they were applicable to surveys in general or attributable specifically to serosurveys. Finally, we calculated the average cost per cluster and participant. RESULTS: We estimated the total nested serosurvey cost was US $68,558 to collect dried blood spots from 658 participants in one province in Zambia. A breakdown of the cost by serosurvey phase showed data collection accounted for almost one third of the total serosurvey cost (32%), followed by survey preparation (25%) and biospecimen collection (20%). Analysis by input categories indicated personnel costs were the largest contributing input to overall serosurvey costs (51%), transportation was second (23%), and field consumables were third (9%). By combining the serosurvey with a vaccination coverage survey, there was a savings of $43,957. We estimated it cost $4,285 per average cluster and $104 per average participant sampled. CONCLUSIONS: Adding serological specimen collection to a planned vaccination coverage survey provided a more direct measurement of population immunity among a wide age group but increased the cost by approximately one-third. Future serosurveys could consider ways to leverage existing surveys conducted for other purposes to minimize costs.

Seroprevalence of measles, mumps, rubella, and varicella zoster virus antibodies among healthcare students: analysis of vaccine efficacy and cost-effectiveness.

OBJECTIVE: The aims of this study are to determine the seroprevalence for measles, mumps, rubella, and varicella zoster virus (VZV) in a cohort of nursing students, to evaluate vaccination response rates of nonimmune students, and to calculate the cost of vaccinating students based on seroprevalence screening. METHODS: A cross-sectional study was conducted August 2015-November 2016 among 326 healthy nursing students aged 14.1-18.1 years. Serum IgG antibodies were measured by ELISA. Results were analyzed by the Chi-square test; a p-value of < 0.05 was considered statistically significant. RESULTS: The number of seropositive participants (%) was 308 (94.5%) for rubella, 295 (90.5%) for VZV, 244 (74.9%) for measles, and 219 (67.2%) for mumps. A significant correlation was found between measles IgG and age. A relationship was also observed between VZV IgG and kindergarten attendance. Response rates to measles, rubella, VZV, and mumps vaccination were 96%, 92.3%, 87.5%, 78.8%, respectively. The total cost of vaccination after IgG screening was less than vaccination without screening. CONCLUSIONS: In this study, participants' immunity to measles and VZV was low. Prevaccination serological screening was cost-effectiveness method for preventing measles, mumps, rubella, and varicella infections. We believe that administering booster measles, mumps, and rubella (MMR) vaccine doses or developing a special MMR vaccination strategy for at-risk groups may prevent MMR outbreaks.

Epidemiology of rubella virus cases in the pre-vaccination era of Ethiopia, 2009-2015.

BACKGROUND: Rubella is a common mild rash illness caused by rubella virus. The majority of infections occur in children and young adults. The infection is the cause of a serious birth defect known as Congenital Rubella Syndrome (CRS) when a woman acquires infection early in pregnancy. Ethiopia has not yet established rubella virus surveillance and has not yet introduced rubella vaccine into the routine immunization program. We characterize the epidemiology of laboratory confirmed rubella virus cases collected through measles surveillance from 2009 to 2015 to better understand the burden of the disease in the country. METHODS: A descriptive analysis was made to characterize rubella cases reported through the national measles case based surveillance system. The measles case definition was used to capture potential rubella cases. A suspected measles case was a person with generalized rash and fever with cough, or coryza or conjunctivitis. Those cases whose sera were negative for measles IgM antibodies were tested for rubella IgM antibody. A confirmed rubella case was a person who tested positive for rubella IgM. Only laboratory confirmed rubella cases were analyzed in this article. RESULTS: Between 2009 and 2015, a total of 28,284 serum/plasma samples were collected and tested for measles IgM antibody and 11,151 (39.4%) were found positive. A total of 17,066 measles IgM negative or indeterminate samples were tested for rubella virus IgM and 2615 (15.3%) were found positive during the same period. Of 2615 confirmed rubella cases, 52.2% were females. The age of confirmed cases ranged from one month to 42 years with a mean age of 7.3 years. Three-fourth of all confirmed rubella cases were aged less than 10 years. The number of laboratory confirmed rubella cases linearly increased from 83 in 2009 to 856 in 2013 but dropped to 222 and 319 in 2014 and 2015 respectively. Higher number of cases occurred in the hot dry season (January through June) and in the central and western part of Ethiopia with 127 lab-confirmed outbreaks in the study period. CONCLUSIONS: Based on our analysis, rubella was found to be endemic throughout Ethiopia. Children below the age of 10 years were the most affected. The burden of rubella cases varied from year to year but had a seasonal peak in March. To better understand the magnitude of rubella prior to vaccine introduction, establishing rubella surveillance system, conducting sero-prevalence studies among child bearing age females and establishing CRS sentinel surveillance among young infants are critical.

[Assessment of measles diagnostic from gingival fluid in Côte d'Ivoire]. / Évaluation du diagnostic de la rougeole à partir des fluides gingivaux en Côte d'Ivoire.

After the adoption of the Global Initiative for Measles Elimination in 2001, Côte d'Ivoire has created monitoring case by case. Thus, the diagnosis of measles from the gingival fluid was implemented, through a pilot project. This study aimed to evaluate the performance of this diagnostic test. We conducted a cross-sectional survey, in four health districts of Abidjan, during a period from July 2010 to December 2012. The study consisted in collecting gingival fluid and serum samples in all suspected measles children. These samples were analyzed by ELISA test at Pasteur Institute of Côte d'Ivoire. Standard formulas were used to calculate sensitivity, specificity, positive predictive value and negative predictive value of oral fluid compared to serum taken as the "gold standard" and confidence intervals were estimated with error alpha risk (α =0.05). The concordance of kappa coefficient (k) was used to estimate agreement level between the results of oral fluid analysis and those of serum. The sensitivity and specificity of the test were 98% and 82% respectively while the positive predictive value and the negative predictive value were 84% and 98%. The comparison of oral fluid with the reference test showed high agreement, between 0.61 and 0.80. The diagnostic test on gingival fluid is acceptable because its sensitivity, specificity and negative predictive value had high level. Therefore it can be extended to all sanitary districts.

Comparative Estimates of Crude and Effective Coverage of Measles Immunization in Low-Resource Settings: Findings from Salud Mesoamérica 2015.

Timely and accurate measurement of population protection against measles is critical for decision-making and prevention of outbreaks. However, little is known about how survey-based estimates of immunization (crude coverage) compare to the seroprevalence of antibodies (effective coverage), particularly in low-resource settings. In poor areas of Mexico and Nicaragua, we used household surveys to gather information on measles immunization from child health cards and caregiver recall. We also collected dried blood spots (DBS) from children aged 12 to 23 months to compare crude and effective coverage of measles immunization. We used survey-weighted logistic regression to identify individual, maternal, household, community, and health facility characteristics that predict gaps between crude coverage and effective coverage. We found that crude coverage was significantly higher than effective coverage (83% versus 68% in Mexico; 85% versus 50% in Nicaragua). A large proportion of children (19% in Mexico; 43% in Nicaragua) had health card documentation of measles immunization but lacked antibodies. These discrepancies varied from 0% to 100% across municipalities in each country. In multivariate analyses, card-positive children in Mexico were more likely to lack antibodies if they resided in urban areas or the jurisdiction of De Los Llanos. In contrast, card-positive children in Nicaragua were more likely to lack antibodies if they resided in rural areas or the North Atlantic region, had low weight-for-age, or attended health facilities with a greater number of refrigerators. Findings highlight that reliance on child health cards to measure population protection against measles is unwise. We call for the evaluation of immunization programs using serological methods, especially in poor areas where the cold chain is likely to be compromised. Identification of within-country variation in effective coverage of measles immunization will allow researchers and public health professionals to address challenges in current immunization programs.

Cellphone-Based Hand-Held Microplate Reader for Point-of-Care Testing of Enzyme-Linked Immunosorbent Assays.

Standard microplate based enzyme-linked immunosorbent assays (ELISA) are widely utilized for various nanomedicine, molecular sensing, and disease screening applications, and this multiwell plate batched analysis dramatically reduces diagnosis costs per patient compared to nonbatched or nonstandard tests. However, their use in resource-limited and field-settings is inhibited by the necessity for relatively large and expensive readout instruments. To mitigate this problem, we created a hand-held and cost-effective cellphone-based colorimetric microplate reader, which uses a 3D-printed opto-mechanical attachment to hold and illuminate a 96-well plate using a light-emitting-diode (LED) array. This LED light is transmitted through each well, and is then collected via 96 individual optical fibers. Captured images of this fiber-bundle are transmitted to our servers through a custom-designed app for processing using a machine learning algorithm, yielding diagnostic results, which are delivered to the user within ∼1 min per 96-well plate, and are visualized using the same app. We successfully tested this mobile platform in a clinical microbiology laboratory using FDA-approved mumps IgG, measles IgG, and herpes simplex virus IgG (HSV-1 and HSV-2) ELISA tests using a total of 567 and 571 patient samples for training and blind testing, respectively, and achieved an accuracy of 99.6%, 98.6%, 99.4%, and 99.4% for mumps, measles, HSV-1, and HSV-2 tests, respectively. This cost-effective and hand-held platform could assist health-care professionals to perform high-throughput disease screening or tracking of vaccination campaigns at the point-of-care, even in resource-poor and field-settings. Also, its intrinsic wireless connectivity can serve epidemiological studies, generating spatiotemporal maps of disease prevalence and immunity.

Measles epidemiology and its implications for a vaccination programme in Oman.

To describe the epidemiology of measles in Oman and the implications for a vaccination programme, we conducted a retrospective record-based study from 1 January 2000 to 31 December 2003 using data from the national epidemiological surveillance system. All cases notified as suspected measles during the study period were included. Of the 185 notified cases, 19.4% were confirmed measles positive. Blood samples for measles IgM were collected in 97.3% of cases. The mean age of measles cases was 8.0 (SD 10.7) years. The estimated overall incidence rate of measles for the study period was 0.53 per 100,000 person-years. Regression analysis indicated measles was significantly commoner among non-Omanis and children who had not been vaccinated.

[Comparative assessment of determination of measles virus IgG antibodies in blood serum and dried whole blood].

Enzyme immunoassay (Dade Behring Enzygnost diagnostic kit, Germany) was used to estimate the levels of measles virus IgG antibodies in 72 samples of blood serum and eluates of the whole blood dried on the Whatman 3M filter paper. The sensitivity of the dried blood test was 98.4%. The regression analysis showed a high correlation of the results (r2 = 0.89; regression coefficient 0.89). Measles virus IgG antibodies were ascertained to be retained in the dried blood at room temperature long (for at least 2 years). After 2-year storage at +4 degrees C, there was a reduction in the concentration of antibodies; however, they were still detectable in 62 (96.9%) out of 64 positive samples. The dried blood test is recommended for wide use to study immunity to measles virus.

Detection of serum neopterin for early assessment of dengue virus infection.

OBJECTIVE: Neopterin is generated and released in increased amounts by macrophages upon activation by interferon-gamma during Th1-type immune response. The potential usefulness of neopterin in early prognostic information of dengue virus infection was investigated. METHODS: Neopterin concentrations were determined in serum samples from 110 dengue fever (DF) patients. The neopterin levels were compared with those in 50 measles and 40 influenza patients; 155 healthy blood donors served as controls. RESULTS: In acute sera of DF patients mean neopterin concentration was 48.2 nmol/L, which was higher than that in patients with measles (mean: 36.3 nmol/L) and influenza (18.8 nmol/L) and in healthy controls (6.7 nmol/L; P<0.001). In the patients with confirmed DF, an early neopterin elevation was detected already at the first day after the onset of symptoms and rose to a maximum level of 54.3 nmol/L 4 days after the onset. Higher increase of neopterin level in DF patients was associated with longer duration of fever and thus predicted the clinical course of the disease. CONCLUSIONS: Neopterin concentrations were found significantly higher in DF patients compared with healthy controls and also with other viral infections (P<0.001) and may allow early assessment of the severity of DF.

Measles seroepidemiology among adolescents and young adults: response to revaccination.

We evaluated the seroprevalence of measles antibody and response to measles reimmunization in 590 previously vaccinated adolescents and young adults; 263 were seronegative. To differentiate between primary and secondary vaccine failure, anti-measles IgM and IgG titres were assessed again 2-4 weeks after revaccination in 144 (105 seronegative, 39 seropositive) individuals: 75 seronegative participants responded to revaccination anamnestically (P < 0.001) and developed immunity, 11 also showed IgM response (probably primary vaccine failure); 38 seropositive participants remained seroprotected without significant increase in antibody titre (P = 0.577). Primary vaccine failure was 4.7%; secondary vaccine failure was 27.1%. After revaccination, 87.3% were seroprotected.

Distinguishing between primary measles infection and vaccine failure reinfection by IgG avidity assay.

In this study in the Islamic Republic of Iran 365 measles cases were evaluated to distinguish between primary infection with measles and reinfection due to secondary vaccine failure. All cases previously confirmed by detection of specific IgM were tested for IgG avidity. A secondary immune response was seen in 18.4% of patients. All unvaccinated patients (16.7%) showed a primary immune response. Of 244 patients with documented vaccination, 75.8% showed a primary immune response and 24.2% showed a secondary immune response, thereby indicating a secondary vaccine failure. Almost all measles reinfections (99%) were seen in patients >10 years old, indicating that vaccination for 10-year-old children is recommended.

Effect of differing immunization policies on circulating measles antibody levels in US and Canadian children.

OBJECTIVE: To examine the effect of differing age-at-immunization policies on measles antibody levels in US children immunized at the age of 15 months compared with Canadian children immunized at the age of 12 months. SUBJECTS AND METHODS: Healthy, volunteer US and Canadian children aged 6 to 11 years who had been immunized with a single dose of the measles vaccine were enrolled from 1991 to 1993. Measles antibody was measured with a whole-virus, measles-specific IgG enzyme-linked immunoassay. Age, race, sex, country of residence, general health status, age at time of measles immunization, and time from immunization to sampling were recorded. RESULTS: Of the 1052 children enrolled in the study, US children (n=719) had a significantly higher measles seroprevalence (87%) compared with Canadian children (n=333) (76%; P<.001). After adjustment for time from immunization and age at immunization, the differences in seropositive rates were no longer significant (odds ratio [OR], 1.53; 95% confidence interval, 0.87-2.69; P=.15). We found a significant dose-response relationship between age at the time of immunization and the odds of being seropositive after immunization, with ORs varying from 1 with immunization at 13 months or younger to 2.30 with immunization at 16 months of age (P=.01). CONCLUSIONS: The current US policy of immunizing with the first dose of measles at the age of 12 months may be less effective than a policy of immunizing at 12 to 15 months of age. These findings may be highly significant as we move toward an era in which measles exposure may be rare and policies are developed to eradicate measles.

Comparison of capillary blood versus venous blood samples in the assessment of immunity to measles.

Seroepidemiological investigations are essential for assessing the efficacy of measles vaccination programmes. However, when large-scale sampling is needed, a major difficulty is the problem of taking venous blood, especially in children. An alternative method is the collection of capillary blood samples spotted on filter papers. The eluted extract from these 'blood' spots can be used instead of serum samples for measles laboratory diagnosis or investigations. Measles antibody detection is readily carried out by ELISA on serum samples. The same technique can be used on eluates from capillary blood spots. Measles antibody titres determined on matched serum and blood spot samples from 27 children were compared. A strong correlation was found between the results obtained with the two methods of blood sampling.

Cost effectiveness of prevaccination screening of health care workers for immunity to measles, rubella and mumps.

OBJECTIVES: To determine the value of infection and vaccination histories as predictors of immunity to measles, rubella and mumps, and to compare the costs of various screening strategies with the cost of universal vaccination of health care workers. SETTING: Staff employed by a Sydney children's hospital. METHODS: Histories of measles, rubella and mumps infection or vaccination were compared with the results of serological testing to determine which historical statements had high positive predictive values (PPV) for immunity. Using this, we devised three prevaccination screening strategies and compared their costs with the cost of universal staff vaccination. RESULTS: Of 235 participants, 98.3% were serologically immune to measles, 96.6% to rubella and 83.0% to mumps. Historical statements indicating immunity with a PPV of more than 95% were histories of measles or of rubella vaccination, and personal recollection of mumps infection. Strategies using historical screening were cheaper than universal vaccination, which in turn was cheaper than using serological screening alone. CONCLUSIONS: Among health care workers at occupational risk of measles, rubella and mumps, the need for vaccination can be reduced by combining historical and serological screening. Where screening is felt to impose an administrative burden, a universal vaccination strategy costs 30%-50% more than strategies which use historical screening.

Measles-mumps-rubella immunization of susceptible hospital employees during a community measles outbreak: cost-effectiveness and protective efficacy.

OBJECTIVE: To determine cost-effectiveness and protective efficacy of a program to identify and immunize susceptible hospital employees during a measles outbreak. DESIGN: A cost analysis was made of blind measles-mumps-rubella (MMR) immunization versus directed MMR immunization based on 2,000 employees born after December 31, 1956. A directed MMR immunization program for susceptible employees was instituted. Actual costs of the program were calculated at the conclusion of the program. SETTING: A medical center complex with more than 4,000 employees, two acute care community hospitals, and a tertiary care children's hospital. RESULTS: A directed MMR immunization program was projected to be less expensive than blind immunization ($23,106 versus $70,720). MMR vaccine was administered to 169 of 188 susceptible employees. Actual cost of the directed MMR immunization program was $25,384. CONCLUSIONS: The directed MMR immunization program was cost-effective and prevented secondary cases among hospital employees during a community measles outbreak.

Measles immunity in employees of a multihospital healthcare provider.

OBJECTIVE: To assess the potential for nosocomial measles transmission by measuring seropositivity among healthcare workers in Utah. DESIGN: Blood specimens were collected for measurement of measles IgG antibody by enzyme immunoassay (EIA). Individuals with undetectable or equivocal antibody levels were considered at risk for infection. Employees were grouped according to the decade of their birth, and analyses of serological findings were done by the Mantel-Haenszel chi-square test for trend. SETTING: The study was performed in a healthcare organization comprised of six urban and 10 rural hospitals. PARTICIPANTS: Employees (n = 5825) were tested regardless of age, history of disease, or immunization. RESULTS: There were 599 employees (10.3%) who were nonimmune. A trend showing age-related differences in immunity was not noted among employees born prior to 1957 (4.7% nonimmune). However, for employees born after that time, there was a significant age-associated increase in the percentage of susceptible individuals (P = 0.00001). The rate of susceptibility was 8.1% for individuals born between 1957 and 1959, 16.3% for individuals born during the 1960s, and 33.7% for those born in the 1970s. CONCLUSIONS: We concluded that employees born after 1960 represent a material risk for transmission of measles in the hospital setting. Despite the low percentage of susceptibility among those born before 1957, the 144 susceptible individuals in this group also are at risk for measles transmission. Thus, during periods of increased measles prevalence, we would recommend screening all healthcare workers regardless of age and vaccinating those who are susceptible.