Human respiratory syncytial virus: an example of why calling them many usually outweighs calling them few, or one

From ICTV 9th Report (2011; now pretty dated)
Paramyxoviridae .[3]

Human respiratory syncytial virus (HRSV) is a beast of a respiratory virus among infants-a leading cause of their hospitalization.

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 a cause of deaths among children too – just 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 also have 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]). Just for context – HRSV was first identified in 1956 so we’re not really on our game here. As usual. Treatment for severe HRSV is therefore mostly to support the patient, 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 just 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 an 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 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 more than one epitope and viruses can have many antigens. Vaccines are often designed to generate an immune response to antigens found on the surface of the virus. But these can change as new generations of virus favour mutations in these regions which let 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 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 vector and DNA vaccines.[12,20] The first clinically trialled HRSV vaccine was based on formalin-inactivated (FI) virus; it was a disastrous failure, resulting in enhanced lung disease upon subsequent natural.[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…

What’s in a name? A lot for HRSV over a lot of years.[4] Click on the table for a bigger image.

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 who are piloting an RSV surveillance strategy based on the Global Influenza Surveillance and Response System in 14 countries in order to develop an evidence-base for informing RSV vaccination policy.[22] This will look more closely at all aspects of what we know and what we need to know about HRSV ahead of rolling out any future vaccines.

Molecular detection and the HRSVs…

Time to first respiratory virus detection episode by virus and subtype/species. ORChID birth cohort study.[23]

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 serious 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 on from 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 as a result of past HRSV infection experiences is unclear. It might become clearer as different vaccine formulations get trialled and the results teased out.

The main message here is: when you hear “blah blah virus”, think “blah blah viruses“!

References…

  1. 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
  2. Respiratory Syncytial Virus Infection in Adults
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88938/
  3. 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
  4. ICTV Taxonomy history: Human orthopneumovirus
    https://talk.ictvonline.org/taxonomy/p/taxonomy-history?taxnode_id=20161069
  5. Respiratory Syncytial Virus Infection in Adults
    https://www.ncbi.nlm.nih.gov/pubmed/16038573
  6. Respiratory Syncytial Virus Infection in Elderly and High-Risk Adults
    https://www.ncbi.nlm.nih.gov/pubmed/15858184
  7. Respiratory Syncytial Virus Infection in Older Adults:An Under-Recognized Problem
    https://www.ncbi.nlm.nih.gov/pubmed/25851217
  8. Respiratory Syncytial Virus Genetic and Antigenic Diversity
    https://www.ncbi.nlm.nih.gov/pubmed/10627488
  9. Antigenic characterization of respiratory syncytial virus strains with monoclonal antibodies.
    https://www.ncbi.nlm.nih.gov/pubmed/2579169
  10. Two distinct subtypes of human respiratory syncytial virus
    https://www.ncbi.nlm.nih.gov/pubmed/2413163
  11. 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
  12. 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
  13. An Overview of Respiratory Syncytial Virus
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999198/
  14. How we change the organisms that infect us
    http://theconversation.com/how-we-change-the-organisms-that-infect-us-74625
  15. 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
  16. Simultaneous Detection, Subgrouping, and Quantitation of Respiratory Syncytial Virus A and B by Real-Time PCR
    https://www.ncbi.nlm.nih.gov/pubmed/12517840
  17. Bats host major mammalian paramyxoviruses
    https://www.nature.com/articles/ncomms1796
  18. 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
  19. Respiratory Syncytial Virus: The Influence of Serotype and Genotype Variability on Clinical Course of Infection
    https://www.ncbi.nlm.nih.gov/pubmed/28783078
  20. Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop
    https://www.ncbi.nlm.nih.gov/pubmed/27566900
  21. Clinical profiles of respiratory syncytial virus subtypes A and B among children hospitalized with bronchiolitis.
    https://www.ncbi.nlm.nih.gov/pubmed/28383391
  22. WHO Global RSV surveillance pilot – objectives
    http://www.who.int/entity/influenza/rsv/rsv_objectives/en/index.html
  23. 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
  24. 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
  25. Two distinct subtypes of human respiratory syncytial virus
    https://www.ncbi.nlm.nih.gov/pubmed/2413163
  26. ICTV Virus Taxonomy Profile: Pneumoviridae
    http://jgv.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.000959#tab2
  27. Universal influenza virus vaccines and therapeutic antibodies
    https://www.sciencedirect.com/science/article/pii/S1198743X17300976
  28. RSV Vaccine and mAb Snapshot
    https://www.path.org/publications/detail.php?i=2747
  29. 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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