In 2012, DRC had an estimated population of 78.1 million persons, 3.1 million live births, and 14.7 million children aged <5 years [14]. The DRC health system has 513 zones de santé (health districts) in 11 provinces. Challenges for vaccination include a large target population, poorly accessible areas, complex logistics, a lack of government funding, weak health systems, civil unrest, and displaced persons [15–17]. The number of displaced persons peaked in 2013, with 2.9 million internally displaced persons (IDPs) in the eastern and northern provinces of DRC and 438,869 Congolese in other African countries [18–21]. The last population census was conducted in 1981 making estimation of the vaccination target population challenging.

To assess measles vaccination coverage in comparison with AFR indicator targets, we calculated MCV1 administrative coverage for 2004-2012 at the national, provincial, and district levels by dividing the reported number of MCV1 doses administered by the number of targeted children aged <12 months, according to the DRC Ministry of Public Health (MOPH), multiplied by 100 (national target: >90%; district target: >80%). The number of districts reporting >80% MCV1 coverage was divided by the number of districts expected to report and multiplied by 100 (target: 100%) [22]. We reviewed WHO-United Nations Children's Fund (UNICEF) annual estimates of national MCV1 coverage among children aged <12 months, and population-based survey estimates of national and provincial MCV1 coverage among children aged 12-23 months during 2004-2012 [23–27]. We reviewed implementation dates, administrative coverage, and survey results from SIAs and outbreak response immunization (ORI) during 2002-2012; the AFR target of >95% SIA coverage in all districts could not be assessed due to unavailable data [22].

Through IDSR, aggregate numbers of suspected measles cases and deaths were reported weekly from districts to the national level [28]. Through measles case-based surveillance, suspected measles cases were investigated using a case investigation form and laboratory testing of a blood specimen at the National Institute for Biomedical Research in Kinshasa [29]. Specimens were tested using standard enzyme-linked immunosorbent assays for measles-specific immunoglobulin M (IgM) antibodies; specimens with a negative or indeterminate result were tested for rubella-specific IgM (Enzygnost ELISA^™, Siemens Healthcare Diagnostics Products, Marburg, Germany). A suspected measles case was defined as an illness with maculopapular rash and fever and one or more symptoms of cough, coryza, or conjunctivitis, or where a clinician suspects measles. A laboratory-confirmed measles case was defined as a suspected measles case with a positive laboratory test result for measles-specific IgM in the absence of measles vaccination within 30 days of specimen collection. An epidemiologically-linked case was defined as a suspected measles case having contact (or living in the same district) with a laboratory-confirmed measles case whose rash onset was within the preceding 30 days. A clinically-compatible case was defined as a suspected measles case without a laboratory test result or established epidemiological link. We classified all laboratory-confirmed, epidemiologically-linked, and clinically-compatible measles cases as confirmed measles cases.

We analyzed de-duplicated IDSR and measles case-based surveillance data from 2004-2012. To assess case-based surveillance performance in comparison with AFR targets, we calculated two indicators as follows:1) the number of districts annually reporting ≥1 suspected measles case with a collected blood specimen divided by the number of districts expected to report (target: ≥80%); and 2) the number of suspected measles cases reported annually and “discarded” as non-measles because of a negative test result divided by the estimated population from DRC MOPH, multiplied by 100,000 (target: ≥2.0). Estimated annual measles incidence was calculated by dividing the number of suspected cases reported through IDSR by the estimated annual population from DRC MOPH, multiplied by 1,000,000 (target: <5) [22].

We conducted an epidemiological analysis of the resurgence period, defined as starting in the first month with a confirmed measles outbreak in 2010 and continuing through the end of 2012, using IDSR and case-based surveillance data from July 1, 2010-December 31, 2012. A confirmed measles outbreak was defined as ≥3 laboratory-confirmed cases occurring in a district in one month. We analyzed suspected measles cases and deaths reported through IDSR by date of rash onset, province, and district. Confirmed measles cases reported through case-based surveillance were analyzed by date of rash onset, age, vaccination status, province, and district. Cumulative measles attack rates were calculated by dividing the number of suspected cases reported through IDSR during the resurgence period, or a 6-month subset of the resurgence period, by the estimated 2012 population from DRC MOPH and multiplying by 100,000. Cumulative measles attack rates and confirmed measles outbreaks by district for 6-month periods were mapped. Analyses were conducted using Excel (Microsoft Corporation), SAS version 9.3 (SAS Institute), and ArcGIS (ESRI).

To identify circulating measles virus strains, nasopharyngeal swabs were collected and tested at the National Institute for Communicable Diseases in South Africa. Ribonucleic acid (RNA) was extracted using the QIAamp^® viral RNA mini kit (QIAGEN^®) and amplified by reverse-transcriptase polymerase chain reaction. Amplicons were sequenced and analyzed using Sequencher software (Gene Codes Corporation 4.1.4, Ann Arbor, MI). Phylogenetic analysis of the viral nucleoprotein (N) gene relative to WHO measles reference strains was performed using the maximum likelihood algorithm of MEGA version 5.1 software with bootstrap test of phylogeny [30].

National MCV1 administrative coverage among children aged <12 months increased from 64% to 89%, and WHO-UNICEF estimates of MCV1 coverage increased from 57% to 73% during 2004-2012. National MCV1 coverage among children aged 12-23 months estimated from surveys was 63% in 2007, 67% in 2010, and 75% in 2012. MCV1 coverage survey estimates were lower than reported administrative coverage for comparable years. In all years, MCV1 administrative coverage varied substantially by province and was below the target of >90% at the national level and >80% in all districts (Table 1).

A phased catch-up SIA targeting children aged 6 months-14 years was implemented during 2002-2006 (median reported administrative coverage by province: 96%; range: 73%-102%), and a phased follow-up SIA targeting children aged 6-59 months was completed during 2006-2010 (median reported administrative coverage: 99%; range: 92%-113%). A 4-year gap between these SIAs occurred in three provinces (Nord Kivu, Kasaï Oriental, and Bandundu). In 2009, another phased follow-up SIA was initiated in Nord Kivu (reported administrative coverage: 112%); however, the phase planned for 2010 was not implemented, leading to a 4-5 year gap between SIAs in five provinces (Kasaï Oriental, Kasaï Occidental, Katanga, Maniema, and Sud Kivu) and a missed cohort of children born in 2006 in Kasaï Oriental (Figure 1 and Table 2). After the start of the 2010 outbreaks, the entire country was covered by a combination of subnational measles follow-up SIAs and ORIs targeting children aged 6-59 months or 6 months-14 years during 2011-2012 (median reported administrative coverage: 101%; range: 93%-112%) (Figure 1 and Table 3).

During 2002-2012, ≤95% administrative coverage was reported from ≥1 measles SIA in eight of 11 provinces (Figure 1). Availability of SIA coverage estimates from surveys during this period was limited. Coverage survey estimates for SIAs implemented in 2006, 2007 and 2011 were >95% in Kinshasa, Bandundu, Nord Kivu, and Maniema, and 94% in Kasaï Occidental, Katanga, and Maniema (Table 2, Table 3). Coverage survey estimates for ORIs implemented during 2010-2012 were >95% in Equateur, 92%-95% in Kasaï Occidental and two ORIs in Maniema, and 68% in Katanga (Table 3). In general, SIA and ORI coverage survey estimates were lower than reported administrative coverage (Table 2, Table 3).

Measles case-based surveillance did not meet both annual performance indicator targets during 2004-2012. The number of suspected measles cases reported through case-based surveillance (16,789) was 3.6% of the total reported to IDSR (459,326); the number of suspected measles deaths reported through case-based surveillance (52) was 0.6% of the total reported to IDSR (8,400). Suspected measles incidence reported through IDSR did not meet the target of <5 per 1,000,000 population during 2004-2012. During 2006-2009, incidence decreased 96%, from 1,164 to 47 per 1,000,000. During 2010-2011, incidence increased from 73 to 1,769 per 1,000,000, and was 935 per 1,000,000 in 2012 (Table 4).

During July 1, 2010-December 31, 2012, 211,236 suspected measles cases were reported through IDSR and 8,142 were reported through case-based surveillance. Of those reported through case-based surveillance, 4,252 (52%) were confirmed as measles (2,465 by laboratory testing and 1,787 by epidemiological link) and 866 (11%) were laboratory-confirmed as rubella (Figure 2 and Table 4). Of the 4,250 confirmed measles cases with age information, 2,839 (67%) were among children aged <5 years, and 879 (21%) were among children aged 5-9 years; 1,036 (24%) were among unvaccinated persons, and 2,168 (51%) were among persons with missing or unknown vaccination status (Table 5).

The first confirmed measles outbreaks of 2010 were reported in three geographic foci: 1) Lemera district bordering Burundi in Sud Kivu province in July 2010; 2) Sakania district bordering Zambia in Katanga province in August 2010; and 3) Dilolo district bordering Angola in Katanga province in September 2010. During July-December 2010, Sud Kivu and Katanga reported elevated cumulative measles attack rates and had 14 districts with confirmed outbreaks. In 2011, the epidemic peaked with confirmed measles outbreaks reported from 108 districts in all 11 provinces and the highest cumulative attack rates reported in Sud Kivu, Katanga, Maniema, and Kasaï Oriental provinces. In 2012, a second epidemic peak occurred with confirmed outbreaks reported from 126 districts in all 11 provinces and the highest cumulative attack rates reported from Province Orientale and Equateur (Figure 2, Figure 3 A and Figure 3 B).

Measles virus genotype results were available from 47 confirmed measles cases in 13 (6%) of 218 districts that had a confirmed outbreak and 8 (73%) of 11 provinces. Three genetic groups of measles virus strains were detected each, associated with one of the three initial outbreak foci and thereafter clustered geographically. Of 47 measles viruses, 13 (28%) were from a group of B3.1 genotypic strains (B3-RwaAng) related to measles virus previously detected in Rwanda and Angola; these strains were first detected in a Sud Kivu district bordering Burundi and localized to northeastern DRC during the outbreak. Another 20 (43%) were from a group of B3.1 genotypic strains (B3-ZamZimSA) related or identical to measles viruses detected during 2009-2011 in Zambia, Zimbabwe and South Africa [31, 32]; these strains were first detected in a Katanga district bordering Zambia and localized to southern and central DRC. Finally, 13 (28%) were from a group of B2 genotypic strains (B2-AngNamDRC) related to those previously detected in Angola, Namibia, and DRC [13]; these strains were first detected in a Katanga district bordering Angola and localized to southern DRC (Figure 3 B, and Figure 4). One district in Bas-Congo province reported both B3-ZamZimSA and B2-AngNamDRC strains in the third-quarter of 2011 (Figure 3 B).

During the resurgence period, the national cumulative attack rate based on IDSR reporting was 270 cases per 100,000 population. The provinces with high cumulative attack rates (>100 cases per 100,000 population) were Katanga, Maniema, Kasaï Oriental, Province Orientale, Equateur, and Sud Kivu. Among these six provinces, estimated MCV1 coverage in the 2010 survey ranged from 46% to 66% (median: 54%), and four provinces had planned SIAs in 2010 that were not implemented. By contrast, estimated MCV1 coverage in the 2010 survey among the five provinces without high cumulative attack rates ranged from 49% to 91% (median 80%), and one province had a planned SIA in 2010 that was not implemented (Table 1 and Figure 1).