K Ndashe1, S Munjita2, N Tembo3, S Musanka2, B Mumba1
1. Department of Environmental Health, Faculty of Health Science, Lusaka Apex Medical University, Lusaka, Zambia
2. Department of Biomedical Sciences, School of Medicine, the University of Zambia, Lusaka, Zambia.
3. Department of Public Health, School of Health Sciences, University of Lusaka, Lusaka, Zambia.
Correspondence: Kunda Ndashe (ndashe.kunda@gmail.com)
Citation style for this article: Ndashe K, Munjita S, Tembo N, Musanka S, Mumba B. Measles Viruses in Zambia: A Review on Circulating Wild-type Genotypes and Complications with Human Immunodeficiency Virus and control (2006-2016). Health Press Zambia Bull. 2019;3 (1); pp 7-14.
This work has been adapted from the original article “[ IMeasles Viruses in Zambia: A Review on Circulating Wild-type Genotypes and Complications with Human Immunodeficiency Virus]” by [Kunda Ndashe, Samuel Munjita, Novan Tembo, Sody Musanka, Bernadette Mumba and with input from the Journal of Preventive and Rehabilitative Medicine ]. Vol. 1, No. 1, 2018, pp. 5-11. doi: 10.21617/jprm.2018.0101.1
Measles is a highly contagious disease that most commonly affects children. The disease continues to record morbidity and mortality among infants in Zambia. We searched online databases such as PubMed, Scopus, Google Scholar, and National Center for Biotechnology Information (NCBI) database and ISI Web of Science and critically reviewed appropriate publications to extract consistent findings, the wild-type MeV present in Zambia, the complications of Measles and the Human immunodeficiency Virus and the control of Measles in Zambia. We included 18 research articles and 2 epidemiological bulletins in the synthesis. From the search of the NCBI database a total of 80 nucleotide sequences of 48 MeV isolates were obtained, 34 sequences (25 MeV isolates) from Zambia and 46 sequences (23 MeV isolates) WHO reference strains. Out of the 34 sequences from Zambia, 9 and 25 were H-gene and N-gene nucleotide sequences, respectively. This study identified 3 MeV genotypes in Zambia (B2, B3 and D2) spatially distributed in Lusaka, Ndola, Kitwe, Mwense and Samfya. Infants born from women who are HIV-1 seropositive had lower maternal antibodies and post initial vaccination antibodies to measles in HIV-1-infected infants waned off rapidly. The review re-emphasized the need for supplemental immunisation activities which include second opportunity to immunisation and case-based surveillance.
Key words: Measles virus, genotypes, control, Zambia
1. Introduction
Measles is a highly contagious disease that most commonly affects children. It is caused by an enveloped nonsegmented, negative stranded RNA Measles virus (MeV) of the genus Morbillivirus, family Paramyxoviridae [1]. The MeV genome encodes a total of eight proteins. The six structural proteins are the nucleocapsid protein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), attachment protein (H), and the large error-prone RNAdependent RNA polymerase protein (L) [2]. Two additional nonstructural proteins (C and V) are encoded in the P transcription unit. While the C protein is translated from an overlapping reading frame within the P gene, the V protein is initiated from the same start codon as P, but a frame-shift is created by mRNA editing [3]. The outcome is that P and V share an N-terminal domain of 231 amino acids, but differ in their C-terminal domains (276 and 69 amino acids, respectively). The N and H gene sequences are most commonly used for genetic characterization of wild-type MeV [4]. The World Health Organisation (WHO) currently recognizes 8 clades, designated A, B, C, D, E, F, G, and H. Within these clades, there are 23 recognized genotypes, designated A, B1, B2, B3, C1, C2, D1, D2, D3, D4, D5, D6, D7, D8,D9, D10, E, F, G1, G2, G3, H1, and H2, and 1 provisional genotype, d11 [5].
In the developed world, measles immunisation programmes have reduced the number of cases reported annually to negligible levels [6]. Nonetheless, measles remains a major health problem in densely populated urban communities in sub-Saharan Africa [7]. In Zambia, measles is endemic with transmission peaks occurring between August and December, despite the relentless efforts of immunisation [8]. Since 1992, MeV has been isolated from children admitted to hospital in Lusaka, Zambia. Between 1992 and 1995, the University Teaching Hospital in Lusaka clinically diagnosed 1066 children with measles of which 203 (19.0%) were less than the 9 months of age which is the recommended time for measles vaccination in Zambia [8]. In another study conducted in Zambia, out of 277 children with clinical measles that were admitted to the University Teaching Hospital, of 149 samples tested, 132 (88.6%) were positive for IgM antibody while 14 (20.9%) of 67 samples, measles viruses were isolated [9]. The latter study highlights the importance of confirmatory tests in the diagnosis of measles to avoid misdiagnosis, since other clinical conditions may cause similar symptoms to measles. Genetic analysis of MeV in a region helps document the effectiveness of control measures. In areas that have endemic transmission of measles, virologic surveillance of cases detects a limited number of genotypes while in areas where endemic transmission of virus has been interrupted, a variety of genotypes are detected, reflecting the multiple sources of imported viruses [10]. The virologic surveillance information has shown that vaccination programs can reduce the number of co-circulating chains of transmission and eventually interrupt measles transmission [11]. However, viruses are continually being introduced from external sources, and if the number of susceptible individuals increases, sustained transmission of the newly introduced viral genotype is possible. This results in what appears as a rapid change in the endemic genotype [12, 13]. The genetic stability of MeV is exceptionally high, and it has been observed that it undergoes remarkably little sequence variation over long periods of time, both in laboratory settings and in the field [14]. Therefore, genetic analysis of MeV in endemic areas such as Zambia helps to document the genotype of circulating virus strains, effectiveness of immunisation and possible introduction of new genotypes from other countries or regions. The article reviews the wild-type MeV present in Zambia, the complications of Measles and the Human immunodeficiency Virus and the control of Measles in Zambia.
2. Methodology
We searched PubMed, Scopus, Google Scholar, and ISI Web of Science (up to November 17, 2017) using the following search terms: “Epidemiology of Measles in Zambia”, “Genotype of Measles Virus in Zambia”, “Measles and Human Immunodeficiency Virus in Zambia”. We supplemented database searches by screening bibliographies of the articles. Two independent reviewers (KN, NT) screened article titles and abstracts to select articles for full-text screening. The reviewers of the current paper assessed full texts independently; in case of disagreement, they consulted a third author (SM), and agreed upon a decision by consensus. We further searched the National Center for Biotechnology Information (NCBI) database for all available nucleotide sequences of MeV isolated from Zambia and WHO reference strains that are used for genetic analysis. The obtained MeV nucleotide sequences were then analysed using Bioedit and MEGA 6 software. Phylogenetic trees were constructed in MEGA6 using the neighbor-joining method with the Kimura two-parameter evolutionary model [15, 16].
3. Results
The primary search identified 58 papers. We removed 24 duplicates. We screened 34 articles to assess eligibility, and excluded 16 that did not meet the inclusion criteria. We included 18 articles in the synthesis. We also included 2 epidemiological bulletins and alert from WHO and CDC. From the search of the NCBI database a total of 80 nucleotide sequences of 48 MeV isolates were obtained, 34 sequences (25 MeV isolates) from Zambia and 46 sequences (23 MeV isolates) WHO reference strains (Table 1). Out of the 34 sequences from Zambia, 9 and 25 were Hgene and N-gene nucleotide sequences, respectively. Topologically, the phylogenetic tree of the N-gene, MeV was separated in 8 groups and the Zambian isolates identified in 3 groups (Figure 1). While phylogenetic tree of the H-gene showed that the Zambian isolates to belong to one group (Figure 2). The Zambian MeV isolates were clustered in the genotypes B2, B3 and D2. Geographical distribution of the MeV in Zambia revealed that genotype B3 was found in Lusaka, Ndola, Kitwe, Samfya and Mwense, genotype B2 in Kitwe and genotype D2 in Lusaka (Figure 3).
Table 1: Measles Virus isolates from Zambia and WHO reference strains
Figure 1: Phylogenetic relationships of the N-gene of MeV detected in clinical patients in Zambia and the WHO reference strains. Phylogenetic analysis was based on 456 bp of the N-gene. Isolate names for nucleotide sequences included in the analyses are given in parentheses
Figure 2: Phylogenetic relationships of the H-gene of MeV detected in clinical patients in Zambia and the WHO reference strains. Phylogenetic analysis was based on 1504 bp of the H-gene. Isolate names for nucleotide sequences included in the analyses are given in parenthese
Figure 2: Phylogenetic relationships of the H-gene of MeV detected in clinical patients in Zambia and the WHO reference strains. Phylogenetic analysis was based on 1504 bp of the H-gene. Isolate names for nucleotide sequences included in the analyses are given in parenthese
4. Discussion
The wild type measles virus genotypes circulating in Zambia Molecular analysis of MeV serves as an important tool to understand the circulating strains of the virus in a region and efforts made in controlling outbreaks through immunisation. This study identified 3 MeV genotypes in Zambia. The genotypes B2, B3 and D2 were isolated from patients clinically diagnosed with measles in Lusaka, Ndola, Kitwe, Mwense and Samfya. The genotype B3 was common in all the 5 districts while B2 and D2 genotypes were unique to Kitwe and Lusaka, respectively. The finding of this review agrees with other workers that have reported MeV in Zambia. Rota and Bellini (2003) and Riddell et al (2005) reported that the genotype D2 was circulating in Zambia and South Africa while Rota et al (2011) further revealed that between 2007 and 2009, 21 genotype B2 sequences were reported from the Democratic Republic of the Congo, Zambia, and Angola [11, 17, 18]. Results of the study further revealed that the genotypes were identified between 2006 and 2014 after Zambia had adopted strategies to accelerate measles control, which included conducting case based surveillance [19]. The complications of Measles and the Human immunodeficiency Virus The co-infection of measles and Human immunodeficiency Virus (HIV) has resulted in complications in the immunisation of the former. It has been reported that infants born to women infected with HIV have lower titres of maternal antibodies to MeV and are at higher risk of contracting measles before the mandatory age of vaccination which is at 9 months in most sub-Saharan countries [20, 21]. Moss et al (2007) in a study in Lusaka reported that HIV-1–infected Zambian children developed antibody levels considered to be protective after measles vaccination at approximately 9 months of age, with comparable frequency to that achieved by HIV-1– uninfected children [22]. The research further revealed that antibody levels to measles vaccine in HIV-1-infected children waned off rapidly surviving up to 2 to 3 years. Scott et al (2007) also reported that levels of maternal antibodies to MeV were lower during the first 9 months of life in Zambian infants born to HIV-1–infected women than in infants born to uninfected women furthermore these levels were lower in HIV-1–infected infants than in HIVseropositive but uninfected infants [23]. Therefore, the HIV-1- infected infants are at increased risk of measles before the mandatory age of routine vaccination at 9 months but are also less likely to have levels of maternal antibodies that would neutralize measles vaccine virus. The World Health Organisation (WHO) recommends a second measles vaccination for all children, either through repeated campaigns or a routine second dose [24].
Measles Control in Zambia
Before 2003, Zambia controlled measles through single dose administration of the measles containing vaccine (MCV) to infants at age of 9 months [19]. Between 1992 and 1999, an average of 11,787 suspected measles case were reported annually, ranging 5, 983 in 1998 to 23, 518 in 1999 [19, 26]. During the same period the national measles immunisation coverage ranged from 61% in 1993 to 93% in 1996. In the quest of controlling measles outbreaks, in 2003, Zambia adopted a strategy of supplemental immunisation activities (SIA) which included strengthening routine vaccination, providing a second opportunity for measles immunisation for all children between 9 months and 4 years, and conducting case-based surveillance [25]. Since it was reported by Moss et al (2007) that MeV antibody titres wane off rapidly in HIV-1- infected children, the second opportunity for measles immunisation offers booster vaccination for prolonged protection against the disease. Lowther et al (2009) reported that 3 years after a successful SIA that markedly decreased incidence and mortality of measles in Zambia, 84% of children within the study townships had a history of measles immunisation and only 67% had detectable antibodies to MeV in oral fluid samples [27]. This result suggested a build-up of susceptible children and a population at risk for measles outbreaks. It was observed that HIV-1-infected children did not contribute substantially to the pool of susceptible children. In 2016 the Ministry of Health (MoH) in its continued efforts to improve child health introduced the Measles Rubella vaccine (MR) in the national routine immunisation system. The vaccine was given to children at the same age as measles vaccine for the first and second doses at 9 months and 18 months respectively during routine immunisation [28]. The introduction of MR vaccine was a necessary step to accelerate progress towards achieving the global goal of measles and rubella elimination by the year 2020 set by the Measles and Rubella Initiative (M&R) Initiative [28]. Zambia reported improvements in under 5 mortality declining from 168 deaths per 1000 live births in 2002 to 75 deaths per 1000 live births in 2014 and are directly attributed to sustained immunisation coverage and other child health interventions [29].
5. Conclusion
Continued monitoring of the MeV genotypes in clinically diagnosed cases is necessary to document the circulating wild-types in order to monitor the efforts of immunisation campaigns. Zambia is well vested with human resource and laboratory capacity to conduct the routine MeV surveillance. Infants born from women infected with HIV1 should be given the first MeV vaccine at 6 months of age because they have lower levels of MDA to Measles. As recommended by WHO a second opportunity for measles vaccination for all children is necessary, because of the reported waning immunity among HIV-1–infected children. Therefore, sufficient resources ought to be allocated towards surveillance and vaccination campaigns by the Ministry of Health (MoH) in Zambia.
Recommendations
Knowledge gaps in the epidemiology of measles over an extended period need to be addressed in the elimination of the disease in Zambia. This information is incredibly valuable as predictable epidemiological patterns emerge as measles elimination is approached and achieved. These critical features, including the source, size and duration of outbreaks, the seasonality and age-distribution of cases, genotyping pointers and effective reproduction rate shall be necessary in the control of the disease.
Author contributions
K.N conceived of the research idea. K.N and SM1 developed the theory and performed the computations. N.T and SM2 verified the analytical methods. BM. encouraged K.N. to investigate [control of measles] and supervised the findings of this work. All authors discussed the results and contributed to the final manuscript.
Acknowledgements
We would like to thank Drs. Oswell Khondowe and Margaret Mweshi for the constructive criticism and guidance during the preparation of the manuscript.
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