Human respiratory syncytial virus (HRSV) is a beast of a respiratory virus among infants-a leading cause of their hospitalization.
Paramyxoviridae .[3]
One estimate reported the worldwide infection of 33.8 million infants younger than 5 years of age, with 66,000-199,000 deaths in a single year.[19]
HRSV is also a cause of death among children – check out its recent role in global lower respiratory tract disease and death.[1]
Most children have been infected by HRSV by the time they are 18 months old.[19]
HRSV infects ciliated airway cells and creates a lot of inflammation, mucous and cell debris when in the lower respiratory tract.[13] HRSV also has bovine and bat relatives.[17]
Of course, HRSV also infects adults, where it can have a serious and under-recognised impact among the elderly (a growing population) and those with pre-existing disease.[5,6,7]
HRSV can reinfect us throughout life.
There are no licensed vaccines or antivirals (ribavirin is clinically approved, but not great.[12]), but there is an expensive preventative monoclonal antibody for high-risk patients, Synagis (Palivizumab; cannot treat serious infections[28]). For context, HRSV was first identified in 1956, so we’re not on our game here as usual. Therefore, treatment for severe HRSV is mostly to support the patient in managing their symptoms.
Is there just one “HRSV”?
HRSV is not just one virus; it’s a few viruses – the HRSVs, really. Most viruses exist in this way, but for simplicity’s sake, we talk about them as a single entity. But in doing that, we overlook one major reason why we get reinfected. Let’s take a look at the ways we’ve named HRSV and how many viruses there might be….
ASIDE: The reality here is that even within us during an “HRSV infection” – or infection by any virus – there will be a host of subtly different mutant virus populations (quasispecies) battling it out; we may even be infected by a bunch of subtly different virus variants, to begin with.
The replication of different viruses is affected by many factors and forces; all fine-tuned through genetic change. Random mistakes, or mutations, are thrown up during each viral replication cycle (infection>>replication>>release, rinse and repeat), and while mostly unhelpful, sometimes these mistakes are beneficial to the virus. A new virus with a mutation that protects it from a drug that lets it replicate in the nose instead of the lung or leads to it being able to dodge our immune defences may become the dominant (most common) virus of the thousands of newly replicated viruses we release.
These are the better-adapted viruses and are more likely to be transmitted to other people.[14]
How the immune response recognises HRSV differences as a way to name HRSV…
Based on the way humans (and small animals) respond to infection (and inoculation), early research found that HRSVs from human infections isolated using virus culture techniques could be divided into two antigenically distinct groups or subtypes of viruses called HRSV A (formerly group 1, for example, the RSV Long and A2 strains) and HRSV B (formerly group 2, for example, B1 and 9320 strains).[24,25] This began back in the 1960s, so we’ve known this much for over 50 years.
ASIDE: What is this antigen we speak of? An antigen is a molecule that is recognised by our immune system. It can trigger the production of an antibody (via B cells) that binds to it or a T cell response (after antigens are presented to the T cell in a special way; not getting into this here). The part of an antigen that is recognised by a single antibody is called the antigenic determinant or epitope. An antigen can have multiple epitope, and viruses can have many antigens. Vaccines are often designed to generate an immune response to antigens found on the virus’s surface. But these can change as new generations of virus favour mutations in these regions, letting the virus escape from ‘immune pressures’. Universal influenza vaccines will aim for immune responses to less variable regions, often inside the virus or protected from immune pressures, whereas HRSV vaccines focus on the surface proteins.[27,28]
HRSVs didn’t always seem to separate out that way when tested using mixed human sera rather than animal sera. When monoclonal (MAbs; specific for a single epitope) antibodies were applied, things changed.[8,24] Use of MAbs revealed that the attachment glycoprotein (G) was the major subtype-defining protein and that two subtypes did indeed exist.[9,10,25]
ASIDE: Vaccine studies in rodents supported that the differences between subtypes were focused on G. A single subtype fusion (F) protein-based vaccine was less picky and could protect rodents from lung replication of the virus from the other subtype.[8] Earlier studies set the scene for vaccines that would need to specifically cater to both virus subtypes in some way. The F protein remains a focus for vaccine and treatment options development alongside a range of live attenuated vaccine (LAV) candidates, protein-expressing particles, gene-based vectors and DNA vaccines.[12,20] The first clinically trialled HRSV vaccine was based on the formalin-inactivated virus; it was a disastrous failure, resulting in enhanced lung disease upon subsequent natural infection.[12,13]
The existence of multiple subtypes means:
- one subtype may escape a maternal antibody response to a different subtype
- infection by “HRSV” will seem to recur, but may be due to different subtypes or even different antigenic variants of the same subtypes
- an HRSV vaccine needs to account for virus variation
Nerdy namers nominate the types…
Precisely where HRSV sits among related but different viruses has changed a lot over time, but especially in the last couple of years.
Where HRSV was once a self-titled species, it is now two viruses within a species recently renamed Human orthopneumovirus, of the genus Orthopneumovirus, family Pneumoviridae.[4] The field of virus naming is run by the International Committee on Taxonomy of Viruses (ICTV) and has had some huge upheavals recently, changing of the guard stuff.
Within the species Human orthopneumovirus sits human respiratory syncytial virus (HRSV).
Genetic sequencing takes a deeper dive…
Those two antigenic subtypes are reflected in groupings that appear after examining genetic sequencing data from different regions of the viruses. But more than that, there are clear signs of subgroups within each antigenic subtype; genotypes. HRSV A was recently recognised as further grouping into HRSV A genotypes A1 and A2 and HRSV B into B1 and B2.[26]
Plans are afoot via the WHO Global Influenza Programme, which is piloting an RSV surveillance strategy based on the Global Influenza Surveillance and Response System in 14 countries to develop an evidence base for informing RSV vaccination policy.[22] This will look more closely at all aspects of what we know and need to know about HRSV before rolling out any future vaccines.
Molecular detection and the HRSVs…
RT-PCR methods can rapidly detect viruses and have been designed to differentiate HRSV As from HRSV Bs.[15,16]
The need to do this is not driven by any type-specific interventions as yet, i.e. finding any HRSV is probably sufficient for routine laboratory needs. HRSV As are detected more frequently, grow better than HRSV Bs in cell culture and in animals and are sometimes linked to a more severe disease, but there are no significant differences between the immune response profiles they elicit in children.[7,11,19].
Conclusion: Viruses not virus…
There is evidence that our body mounts distinct immune responses against at least two groups of HRSV – A and B. But within each of those antigenic groupings, there is lots of genetic variation, a lot of genotypes. The changes leading to this genetic variation are ongoing and can also result in viruses that our immune system may see as a new threat worthy of mounting a new immune response to. Following that comes inflammation and illness.
The extent to which all these genotypes or antigenic variants succumb to or escape from the immune pressure our immune memory brings to bear due to past HRSV infection experiences is unclear. It might become clearer as different vaccine formulations get trialled and their results teased out.
The main message here is: when you hear “blah blah virus”, think “blah blah viruses“!
References…
- Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30396-1/fulltext - Respiratory Syncytial Virus Infection in Adults
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88938/ - Maps of genomic RNAs (3′-to-5′) of viruses in the family Paramyxoviridae
https://talk.ictvonline.org/ictv-reports/ictv_9th_report/negative-sense-rna-viruses-2011/w/negrna_viruses/200/paramyxoviridae-figures - ICTV Taxonomy history:Â Human orthopneumovirus>
https://talk.ictvonline.org/taxonomy/p/taxonomy-history?taxnode_id=20161069 - Respiratory Syncytial Virus Infection in Adults
https://www.ncbi.nlm.nih.gov/pubmed/16038573 - Respiratory Syncytial Virus Infection in Elderly and High-Risk Adults
https://www.ncbi.nlm.nih.gov/pubmed/15858184 - Respiratory Syncytial Virus Infection in Older Adults:An Under-Recognized Problem
https://www.ncbi.nlm.nih.gov/pubmed/25851217 - Respiratory Syncytial Virus Genetic and Antigenic Diversity
https://www.ncbi.nlm.nih.gov/pubmed/10627488 - Antigenic characterization of respiratory syncytial virus strains with monoclonal antibodies.
https://www.ncbi.nlm.nih.gov/pubmed/2579169 - Two distinct subtypes of human respiratory syncytial virus
Similar Cytokine Profiles in Response to Infection with Respiratory Syncytial Virus Type A and Type B in the Upper Respiratory Tract in Infants
https://www.ncbi.nlm.nih.gov/pubmed/18493154 - Progress and Challenges in RSV Prophylaxis and Vaccine Development
https://academic.oup.com/jid/article/208/suppl_3/S177/790306/Progress-and-Challenges-in-RSV-Prophylaxis-and - An Overview of Respiratory Syncytial Virus
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999198/ - How we change the organisms that infect us
http://theconversation.com/how-we-change-the-organisms-that-infect-us-74625 - Applicability of a Real-Time Quantitative PCR Assay for Diagnosis of Respiratory Syncytial Virus Infection in Immunocompromised Adults
https://www.ncbi.nlm.nih.gov/pubmed/12958272 - Simultaneous Detection, Subgrouping, and Quantitation of Respiratory Syncytial Virus A and B by Real-Time PCR
https://www.ncbi.nlm.nih.gov/pubmed/12517840 - Bats host major mammalian paramyxoviruses
https://www.nature.com/articles/ncomms1796 - Respiratory viral pathogens associated with lower respiratory tract disease among young children in the highlands of Papua New Guinea
http://www.journalofclinicalvirology.com/article/S1386-6532(12)00157-6/fulltext - Respiratory Syncytial Virus: The Influence of Serotype and Genotype Variability on Clinical Course of Infection
https://www.ncbi.nlm.nih.gov/pubmed/28783078 - Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop
https://www.ncbi.nlm.nih.gov/pubmed/27566900 - Clinical profiles of respiratory syncytial virus subtypes A and B among children hospitalized with bronchiolitis.
https://www.ncbi.nlm.nih.gov/pubmed/28383391 - WHO Global RSV surveillance pilot – objectives
http://www.who.int/entity/influenza/rsv/rsv_objectives/en/index.html - Timing of First Respiratory Virus Detections in Infants: A Community-Based Birth Cohort Study
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jix599/4638969 - Antigenic Characterization of Respiratory Syncytial Virus Strains with Monoclonal Antibodies
https://academic-oup-com.ezproxy.library.uq.edu.au/jid/article/151/4/626/942189 - Two distinct subtypes of human respiratory syncytial virus
https://www.ncbi.nlm.nih.gov/pubmed/2413163 - ICTV Virus Taxonomy Profile: Pneumoviridae
http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000959#tab2 - Universal influenza virus vaccines and therapeutic antibodies
https://www.sciencedirect.com/science/article/pii/S1198743X17300976 - RSV Vaccine and mAb Snapshot
https://www.path.org/publications/detail.php?i=2747 - Respiratory syncytial virus from Center for Vaccine Innovation and Access
http://sites.path.org/cvia/our-disease-targets/respiratory-syncytial-virus/
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