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REVIEW ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 4  |  Page : 458-464
 

Respiratory syncytial virus infections in India: Epidemiology and need for vaccine


1 Department of Microbiology, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India
2 Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
3 Department of Microbiology, Dr. Baba Saheb Ambedkar Medical College and Hospital, New Delhi, India

Date of Web Publication18-Mar-2019

Correspondence Address:
Dr. Shobha Broor
Department of Microbiology, Faculty of Medicine and Health Sciences, SGT University, Gurugram - 122 005, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_19_5

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 ~ Abstract 

Respiratory syncytial virus (RSV) has been identified as a leading cause of lower respiratory tract infections in young children and elderly. It is an enveloped negative-sense RNA virus belonging to Genus Orthopneumovirus. The clinical features of RSV infection range from mild upper-respiratory-tract illnesses or otitis media to severe lower-respiratory-tract illnesses. Current estimates show that about 33.1 million episodes of RSV-acute lower respiratory infection (ALRI) occurred in young children in 2015, of these majority that is, about 30 million RSV-ALRI episodes occurred in low-middle-income countries. In India, the rates of RSV detection in various hospital- and community-based studies mostly done in children vary from 5% to 54% and from 8% to 15%, respectively. Globally, RSV epidemics start in the South moving to the North. In India, RSV mainly peaks in winter in North India and some correlation with low temperature has been observed. Different genotypes of Group A (GA2, GA5, NA1 and ON1) and Group B (GB2, SAB4 and BA) have been described from India. The burden of RSV globally has kept it a high priority for vaccine development. After nearly 50 years of attempts, there is still no licensed vaccine and challenges to obtain a safe and effective vaccine is still facing the scientific community. The data in this review have been extracted from PubMed using the keywords RSV and Epidemiology and India. The data have been synthesised by the authors.


Keywords: Acute lower respiratory infection, acute respiratory infection, epidemiology, India, respiratory syncytial virus


How to cite this article:
Broor S, Parveen S, Maheshwari M. Respiratory syncytial virus infections in India: Epidemiology and need for vaccine. Indian J Med Microbiol 2018;36:458-64

How to cite this URL:
Broor S, Parveen S, Maheshwari M. Respiratory syncytial virus infections in India: Epidemiology and need for vaccine. Indian J Med Microbiol [serial online] 2018 [cited 2019 Jun 26];36:458-64. Available from: http://www.ijmm.org/text.asp?2018/36/4/458/254408



 ~ Introduction Top


Respiratory syncytial virus (RSV) has been identified as one of the most important causative agents of lower respiratory tract infections (LRTIs) in young children and elderly worldwide.[1],[2],[3] It is one of the most important infections of childhood and is associated with significant morbidity and mortality, especially in low- and middle-income countries (LMIC).[4] Despite huge disease burden due to RSV so far, the development of RSV vaccine has lagged behind. However, in recent years, with the advances in understanding of RSV immunopathology and innovation in immunogen design, a number of RSV vaccines and monoclonal antibodies are in the pipeline.[5] It is important to understand the epidemiology of an infectious disease before vaccine can be launched, and thus all over the world, there has been a surge in studies on RSV epidemiology, including India. This review presents a summary of information available on RSV epidemiology in India.


 ~ Respiratory Syncytial Virus Top


RSV is an enveloped negative-sense RNA virus belonging to the order Mononegavirales, family Pneumoviridae and Genus Orthopneumovirus.[6] The unsegmented RNA is about 15200 nucleotides long and codes for 11 structural and non-structural proteins.[7] The envelope contains glycoproteins G, F and SH of which G protein is the cell-attachment protein and is most variable. F protein is the fusion protein and induces syncytia formation. Both G and F proteins induce neutralising and non-neutralising antibodies. According to the reactivity of RSV with monoclonal antibodies against G glycoprotein, the virus is divided into two major antigenic groups as follows: Group A and Group B.[8] The RSV group A is further subdivided into 14 genotypes, GA1-GA7, SAA1, SAA2, NA1-NA4 and ON1,[9] and the RSV group B has 27 genotypes: BA1-BA 12, BA-C, SAB1-SAB4, GB1-GB4, URU1, URU2, CB-B, CB1, BACCB and BACCA.[10]


 ~ Viruses and Acute Respiratory Infection Top


Acute respiratory infections (ARIs) account for 20%–40% of outpatient and 12%–35% of inpatient attendance in a hospital.[11] Viruses account for 50%–90% of acute LRTI (ALRTI).[12] Majority (80%) of identified viruses include RSV, influenza A and B, human parainfluenza viruses and Human metapneumovirus.[13] Human RSV is the leading cause of LRTIs in infants and younger children worldwide.[14]


 ~ Clinical Features of Respiratory Syncytial Virus Infection Top


The clinical features of RSV infection range from mild upper-respiratory-tract illnesses or otitis media to severe lower-respiratory-tract illnesses. RSV is the most important cause of LRTI that is, bronchiolitis and pneumonia and sometimes croup, especially in young children <1-year old.[15] Infection with this virus occurs during the 1st year of life in 50% of children and 20%–40% of them have signs of LRTI (bronchiolitis or pneumonia).[16] Virus at first multiplies in the nasopharynx and then spreads to the lower respiratory tract, the incubation period is 3–5 days and reinfections are common in both children and adults. The presence of signs of wheeze, chest in-drawing, tachypnoea and crepitation had significantly higher odds of being present in RSV positive versus RSV negative.[14] Underlying medical conditions, such as prematurity, congenital heart disease or chronic lung diseases, are associated with an increased risk of RSV hospitalisation and mortality.[17],[18] Prematurity, low birth weight, male siblings, maternal smoking, history of atopy, no breastfeeding and crowding (≥7 persons in household) have been reported to be significantly associated with RSV-associated acute lower respiratory infection (ALRI) as reported in a meta-analysis of risk factors for RSV.[19]

RSV infections in adults are usually secondary infections and are mild to moderate in severity, unless underlying risk factors are present such as frail elderly living at home or in long-term care facilities, underlying chronic pulmonary disease or circulatory disease and the severely immunocompromised.[20] Infections in immunocompromised and post-transplant individuals can be severe. The mortality rate of RSV in transplant recipients is significantly higher than in the general population. In a 2-year retrospective study, in RSV-positive patients, there was significant morbidity and mortality among haematopoietic stem cell transplant patients (7.3%, 60-day mortality), solid-organ transplant patients (13.3%, 60-day mortality) and chronic obstructive pulmonary disease patients (12.8%, 60-day mortality).[21]


 ~ Global Respiratory Syncytial Virus Epidemiology and Disease Burden Top


Globally, ALRI is the leading causes of morbidity and mortality in under-five children. Human RSV is among the most common pathogen identified in children with ALRI. In a recent meta-analysis, it has been estimated that about 33.1 million episodes of RSV-ALRI occurred in young children in 2015, of these majority that is, about 30 million RSV-ALRI episodes occurred in LMIC, of which about a third occurred during the 1st year of life, whereas in high-income countries (HIC) only an estimated 2.8 million RSV-ALRI episodes occurred, thus the burden of RSV was more than ten times in LMIC and middle-income countries as compared to HIC. RSV-ALRI resulted in about 3.2 million (2.7–3.8) hospital admissions and 59,600 (48,000–74,500) in-hospital deaths in children younger than 5 years. The incidence of severe RSV-ALRI in infants is twice or three times greater than is reported for children <5 years overall. In children younger than 6 months, 1.4 million (UR 1.2–1.7) hospital admissions and 27,300 (UR 20,700–36,200) in-hospital deaths were due to RSV-ALRI of which a large number were in neonates who often present as apnoea or sepsis.[4]

In 2015, RSV-associated ALRI incidence in developing countries was twice that of industrialised countries.[2] However, these estimates are based on limited data from India.


 ~ Acute Respiratory Infection in India Top


About 2.5 million children die each year in India, ~1/5 due to ALRI.[22] ARI accounts for 17%–25% of all deaths in under-fives and ARI mortality is about 27/1000 in rural India.[23] It has been estimated that about 20%–40% of all outpatient visits and 12%–35% of indoor admissions are due to ARIs.[11] The rates of ARI were estimated to be 3.67 attacks/child/year in under-five from rural community near Delhi of which 14.7% were ALRTI.[24]


 ~ Respiratory Syncytial Virus in India Top


The rates of RSV detection in various hospital-based studies mostly done in children vary from 5% to 54% [Table 1].[23],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47] These differences in rates of RSV detection are due to the selection of patients, their age group and the method used for RSV diagnosis. Most of the recent studies, which have used molecular techniques, show rates varying from 15% to 22%. However, studies employing antigen detection methods such as ELISA or immunochromatography have a very high rate of RSV detection, which may be due to the high false positivity of these methods. In a study conducted at AIIMS, New Delhi, it was observed that substantial number of LRTIs in children below 5 years of age is due to viral pathogens in India (44.5%). RSV was detected in 17% of children hospitalised with ALRI by centrifugation-enhanced culture. RSV was a major pathogen (26%) in children with bronchiolitis.[31]
Table 1: Respiratory syncytial virus in hospital-based studies in India (1971-2018)

Click here to view


There have been a few community-based studies in India where also the rates of RSV detection vary from 8% to 15% depending on the methodology used and the study site [Table 2]. The incidence rates of RSV infection in these community studies from Ballabhgarh were 234 (192–281)/1000 child years in the study by Broor et al.[48] and 420 (350–500)/1000 child years in the later study by Krishnan et al.[49] In the previous study, immunofluorescence assay (IFA) was done for RSV detection but later study used real-time reverse transcription-polymerase chain reaction (PCR) for RSV detection which may account for the higher rates seen in the later study. The highest incidence rates were seen in infants in the study by Broor et al.[48] that is, 324/1000 child years. Global estimates of incidence of RSV-associated severe ALRI are 75 (31–180)/10,000 child years.[4] Average annual incidence of RSV-associated hospitalisation/1000 child years from Ballabhgarh among 0–23-month-old children was 7.4, as compared to 0.5 among 24–59 months old signifying that most of the burden of RSV-associated hospitalisation is among children under 2 years of age.[14]
Table 2: Respiratory syncytial virus in community-based studies in India

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 ~ Seasonality of Respiratory Syncytial Virus Top


To optimise the prevention, diagnosis and treatment of RSV infection in a timely manner, knowledge about the differences in the timing of the RSV peak activity in different geographical regions is needed. Globally, RSV epidemics start in the South moving to the North. In a study on global seasonality of RSV, it was observed that RSV waves in Southern hemisphere start between March and June and in the Northern Hemisphere between September and December.[50] Decrease in RSV activity was observed from August to October in the Southern Hemisphere and from February to May in the Northern Hemisphere. However, RSV lingers for a long period (up to 10 months) in countries with humid and rainy season near the equator.[50] In temperate climates, RSV activity correlates with decrease in temperature, whereas in tropical countries, RSV activity is seen mainly in rainy season with some residual activity through the year.[50] The information from middle- and low-income countries on RSV epidemiology and seasonality is scarce as most of these regions lack RSV surveillance networks. To this respect, the WHO through the Global Influenza Surveillance and Response System has implemented a pilot of RSV surveillance based on the influenza surveillance platform, with 14 countries selected covering for each of the WHO regions.

In India, RSV mainly peaks in winter in North India and some correlation with low temperature has been observed.[31],[48] In Odisha, respiratory virus infections showed seasonal variation, with peaks during the rainy season followed by winter season,[44] whereas in Kolkata, RSV infection was predominant during November–February.[34]


 ~ Molecular Epidemiology of Respiratory Syncytial Virus in India Top


Limited studies from India have investigated molecular epidemiology of RSV. These included detection of RSV in clinical samples using modern diagnostic tools such as PCR and real-time PCR. The RSV strains were then characterised by DNA sequencing, followed by phylogenetic, Bayesian and Network analyses. The RSV strains were classified into genotypes by phylogenetic analysis. Both Groups A and B RSV have been reported from India [Table 3].[38],[47],[51],[52],[53],[54] Different genotypes of Group A (GA2, GA5, NA1 and ON1) and Group B (GB2, SAB4 and BA) have been described from India. BA genotype of Group B has 60 bp duplication and ON1 genotype of Group A has 72 bp duplication in the G gene.
Table 3: Molecular epidemiological studies of respiratory syncytial virus from India

Click here to view


The origin or time to most recent common ancestor (tMRCA) and evolutionary rates were determined using Bayesian methods. Two recent studies from New Delhi carried out comprehensive evolutionary dynamics of Groups A and B RSV.[55],[56] This study reported tMRCA of Group A and NA1 genotype to be years 1953 and 2000, respectively. Similarly, Group B originated in years 1955, BA in 1995 and BA9 in 2000. The evolutionary rates of Group A and NA1 genotype were estimated to be 3.49 × 10−3 and 3.56 × 10−3, respectively, in this study. Similarly, the nucleotide substitution rates for Group A, BA genotype and BA9 lineage were estimated to be 4.59 × 10−3, 4.58 × 10−3 and 4.03 × 10−3, respectively. The relation among the haplotypes for NA1 genotype of Group A and BA9 lineage of BA genotype of Group B was determined using network analysis. Further, the molecular analysis of the RSV strains was done by mutational, glycosylation, selection pressure and entropy analyses. Two full genomes of Group A RSV were reported from Pune in 2013.[57]


 ~ Respiratory Syncytial Virus Vaccines Top


The burden of RSV globally has kept it a high priority for vaccine development. After nearly 50 years of attempts, there is still no licensed vaccine and challenges to obtain a safe and effective vaccine is still facing the scientific community.

The epidemiology and burden of RSV disease suggest that there are at least four distinct target populations for RSV vaccines:

  • Infants (<6 months of age) who have the highest risk of severe disease
  • Children >6 months of age to prevent disease in them and reduce potential transmission to younger children and the elderly
  • Pregnant women to protect newborns both by transplacental transfer of antibodies and by blocking transmission
  • Elderly.


Recognition of the importance of RSV as an acute cause of paediatric morbidity and mortality has led to a surge in RSV vaccine and monoclonal antibody development, with more than 16 vaccine or monoclonal antibody candidates currently being assessed in clinical trials. The first candidate vaccine, formalin-inactivated RSV was associated with enhanced disease and two deaths upon subsequent natural RSV infection.[58] This occurred in children under 2 years of age but not in older children, possibly because among the older children prior natural infection established a safer immune response pattern before vaccination. This experience delayed the development of RSV vaccine for many years and it has been difficult to achieve the right balance of safety and immunogenicity/efficacy for RSV vaccines. A number of RSV vaccine candidates are under development or in different phases of clinical trial. These include the following:

  • Live-attenuated RSV vaccines which have been in development for decades. These live vaccines do not cause enhanced disease in RSV-naïve infants. Recent approaches include engineered viruses such as (a) 'knock-out' viruses that are attenuated but still immunogenic, such as the M2-2 deletion mutant that favours transcription over-replication of the genome leading to more protein production but limited virus production and (b) naturally attenuated chimeric viruses combining genes from RSV-related viruses such as Sendai, parainfluenza virus and bovine RSV
  • Protein-based vaccines which include whole-inactivated virus, subunit antigens that associate to form aggregate particles and non-particle-based subunit antigens. These vaccines are mainly for protecting elderly populations from severe disease and are often formulated with an adjuvant. Particle and protein-subunit vaccines are also being developed for immunisation during pregnancy to boost pre-existing immunity to increase transplacental transfer of RSV-specific antibody to infants
  • Replication-competent and deficient Alphavirus, adenovirus and modified vaccinia virus Ankara vectors encoding RSV surface antigens are being developed for use in infant and paediatric populations. These vaccines elicit robust humoral and cellular immunity
  • Nucleic acid vaccines using either plasmid DNA or messenger RNA encoding RSV antigens are being targeted to protect both paediatric and elderly populations. Combination approaches with DNA and protein are also in development
  • RSV monoclonal antibodies include a modified version of the D25 mAb, which is specific for the neutralising epitope in antigenic site Ø on the pre-F confirmation of RSV F protein is being developed for passive prophylaxis in paediatric populations. Genetic modifications that increase potency and half-life may provide protection for an entire RSV season with a single dose.


Overall, 16 RSV candidates are currently advancing through Phase 1 to Phase 3 clinical trials.[5]

Most LMIC, where the RSV disease burden is greatest, have little or no national data and low awareness on RSV as a cause of disease. This gap in knowledge may hamper and delay evidence-based policy decisions with respect to any new RSV vaccine in LMIC. India is one of these countries where RSV infections impose a significant burden among under-five children and are among major causes of pneumonia mortality in India. RSV infections are also a problem among elderly, which is more neglected. The need for RSV vaccine for India is very obvious and crucial, but RSV epidemiology is not well documented in India. There are very few community-based studies describing the burden of RSV disease and hospitalisation. There is a need for teamwork of microbiologists, paediatricians and public health experts to understand the disease burden and seasonality of RSV infections in a vast country like India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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  [Table 1], [Table 2], [Table 3]



 

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2004 - Indian Journal of Medical Microbiology
Published by Wolters Kluwer - Medknow

Online since April 2001, new site since 1st August '04