Question refers to https://www.fool.com/investing/2019/03/01/can-novavax-convince-the-fda-its-vaccine-deserves.aspx
This answer briefly covers
- The need for RSV vaccine(s).
- What’s minimally necessary to unravel how ineffectual rather than effective, neutralizing antibodies get generated.
- Silos and inherent limitations that stymie research into RSV.
The need for RSV vaccine(s)
Novavax RSV candidates were among the earliest to get going so no surprise that they’re the furthest along in the clinical trial pathway (first figure below from 1, 2, 3) nor that they are perhaps the ones most likely to face problems since much more is now known about how RSV subverts immune responses than when Novavax got started with its F protein-based nanoparticle vaccine candidates.
In healthy adults RSV is merely a pesky virus that causes colds but it’s a bane in the very young and the very old who have the highest risk of mortality from more serious complications such as pneumonia (below from 4).
In fact, epidemiological data from countries such as Sweden (5) suggest that RSV is the most common entity causing lower respiratory tract infection in children below the age of 5 so much so that it’s estimated that most children have antibodies to it by 18 months of age even as virtually all of us are estimated to harbor it by 3 years (4). This unmet need defines the need for an RSV vaccine.
What’s minimally necessary to unravel how ineffectual rather than effective, neutralizing antibodies get generated
The path to an effective RSV vaccine is littered with rocks and hard places. Higher risk of more serious infections among RSV vaccinated infants is actually a 50+ year old road bump haunting this effort that has proved serious enough to get its own descriptor, enhanced respiratory disease or ERD (6, 7).
- The very first RSV vaccine to get trialled in the late 1960s, a formalin-inactivated one called FI-RSV, was such a disaster that ~80% of vaccinated infants (16/20) who subsequently caught RSV either developed bronchiolitis or pneumonia and needed to be hospitalized, with two deaths, compared to only 5% of control infants (1/21) (8).
- A similar phenomenon of more severe infections among vaccinated is seen with some Dengue vaccine candidates though that one is accompanied by an in vitro phenomenon called antibody-dependent enhancement or ADE.
ERD, ADE, rather than focus on the specific monikers given to these phenomena, it’s more relevant to understand that a similar mechanism’s at play – such vaccines seem to trigger the generation of antibodies that no doubt bind virus antigens specifically during an infection except they seem to be the unhelpful kind (9). Instead of successfully neutralizing the virus to prevent it from infecting cells, these antibodies seem to do the opposite – help the bound viruses infect cells more efficiently, via a process known as Fc receptor-mediated phagocytosis (10).
Two possibilities could explain this unhelpful process,
- Somehow more cells get infected resulting in more infectious virions than would otherwise be the case, or
- Uptake of viruses bound to such ‘unhelpful’ antibodies somehow leads to the generation of more infectious virions per infected cell.
There are thus two as-yet unsolved mysteries, one at each end of the immune response process that leads to ERD or ADE,
- At the back end, exactly how do antibodies that mediate ERD or ADE abet rather than inhibit these viruses? What attributes make such antibodies different from those that can effectively neutralize viruses – Target specificity (choice of target)? Affinity (for antigen)? Isotype (antibody class) that defines its Fc portion?
- At the front end, how do these ‘unhelpful’ antibodies get generated in the first place? Knowing that is necessary to be able to design vaccine candidates that could explicitly avoid doing so. What kind of CD4+ T cell help is necessary and sufficient to abet or prevent ERD or ADE – antigenic epitopes such T cells bind plus the kind of cytokines such T cells secrete.
Silos and inherent limitations that stymie research into RSV
Answers to such questions require a frank and transparent examination of what is studied and how, which are the source of problems with not just RSV or Dengue but really any interesting immunological puzzle today. In particular, two different types of limitations stymie the effort to better understand RSV-specific immune responses.
- Silos and disproportionate focus on studying immune responses that are fashionable and not necessarily relevant.
- Inherent limitations to studying a strikingly human-specific virus such as RSV.
Silos. A similar phenomenon is at play with vaccine candidates for such dissimilar viruses as RSV and Dengue, meaning the issue necessary to unravel is at heart an immunological and not a virus-specific mystery. Instead, in an example that highlights how silos in biomedical research make it easy to miss the forest for the trees, other than an occasional review (11), immune responses to dissimilar viruses such as Dengue and RSV are rarely discussed together, let alone studied in tandem.
Studying immune responses that are in fashion and not necessarily the most relevant is another unfortunate chronic predilection. Overweening and decades-long focus on innate (non-B and non-T cell) immune responses has been strikingly unproductive with respect to actionable information useful for vaccinology even as it’s generated reams of data while knowledge of CD4+ T cell responses to such viruses remains stunted and rudimentary.
To add insult to injury, as is unfortunately the case far too often these days, study of human CD4+ T cell responses to RSV tends to focus on the kinds of cytokines they secrete (4, 12) with little attention paid to the pieces of antigens they bind that might correlate with either effective (neutralizing) or ineffective (ERD) immunity.
Inherent limitations. Let’s face it – understanding RSV biology faces a perfect storm of natural obstacles as well. The human RSV is highly specific for humans and lacks an animal reservoir in nature (13). Thus, even though a variety of animal models are routinely used as surrogates of human RSV infection (below from 14), they aren’t good ones for it simply because neither do human RSV strains infect them effectively nor do immune responses or human RSV-induced disease phenotypes in these animals accurately recapitulate those observed in their human counterparts.
It’s ethically and technically challenging to study RSV-specific immune responses and the type of disease(s) this virus induces in the lower respiratory tracts of the very young and the very old, the groups most susceptible to serious RSV complications. Instead and rather predictably, researchers have learned more about how healthy adults handle RSV and that too by looking at RSV-specific immune responses in their circulating blood – the old and by now hackneyed ‘ looking under the lamp post’ phenomenon that plagues so much of current biomedical research.
This is particularly a handicap with RSV since circulating blood tends to harbor few RSV-specific T cells anyway, which means the critical gap in knowledge of RSV-specific CD4+ T cells also stays unaddressed. Meantime relatively little is still known about infant RSV disease.
Consider also the outsize influence of Palivizumab, a humanized mAb (monoclonal antibody) against the RSV’s F protein. It prevents disease (is prophylactic) but doesn’t protect once disease is established (isn’t therapeutic) (15). It’s usually given to infants at high risk of serious disease from RSV in the form of passive immunoprophylaxis (monthly injection) during epidemic seasons. An important takeaway from Rx with this mAb is that antibodies alone can protect against severe disease from RSV, a conclusion that has had profound impact on the course of RSV vaccinology.
Most RSV vaccine candidates are trying to mimic Palivizumab’s effect by trying to get their vaccine candidates to generate similar antibodies without really understanding the entire suite of immune responses necessary to generate such an antibody in the first place. Thus, while Palivizumab is truly a godsend for treating RSV complications such as wheeze in pre-term infants, it could also be considered a bane in RSV vaccinology.
Even the ABCD of human CD4+ T cell responses to RSV in terms of their antigen specificity and antigenic preferences (Immunodominance – Wikipedia) remain woefully unexplored even till date. What is known about the exact antigenic specificity/ies and other properties of RSV-specific CD4+ T cells necessary to help an RSV-specific B cell generate a Palivizumab-like neutralizing antibody? Nothing – a case of cart before horse, similar to the problem that besets the fields of HIV and flu vaccinology.
Bibliography
1. RSV Vaccine and mAb Snapshot
2. Rezaee, Fariba, et al. “Ongoing developments in RSV prophylaxis: a clinician’s analysis.” Current opinion in virology 24 (2017): 70-78. Ongoing developments in RSV prophylaxis: a clinician’s analysis
3. Mazur, Natalie I., et al. “The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates.” The Lancet Infectious diseases 18.10 (2018): e295-e311. https://centerforimmunizationresearch.org/wp-content/uploads/2018/08/Karron-RSV-Publication-2018-in-Lancet.pdf
4. Openshaw, Peter JM, et al. “Protective and harmful immunity to RSV infection.” Annual review of immunology 35 (2017): 501-532.
5. Simoes, Eric AF. “Respiratory syncytial virus infection.” The Lancet 354.9181 (1999): 847-852. https://www.ucalgary.ca/paed/files/paed/rsv.pdf
6. Acosta, Patricio L., Mauricio T. Caballero, and Fernando P. Polack. “Brief history and characterization of enhanced respiratory syncytial virus disease.” Clin. Vaccine Immunol. 23.3 (2016): 189-195. https://cvi.asm.org/content/cdli/23/3/189.full.pdf
7. Salpor, Jessica. “A History of Respiratory Syncytial Viral Vaccine Development… What is next?.” (2018). https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=1091&context=creativecomponents
8. KIM, HYUN WHA, et al. “Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine.” American journal of epidemiology 89.4 (1969): 422-434.
9. Delgado, Maria Florencia, et al. “Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease.” Nature medicine 15.1 (2009): 34. Lack of antibody affinity maturation due to poor Toll stimulation led to enhanced RSV disease
10. Acevedo, Orlando A., et al. “Contribution of Fcγ receptor-mediated immunity to the pathogenesis caused by the Human Respiratory Syncytial Virus.” Frontiers in cellular and infection microbiology 9 (2019). Contribution of Fcγ Receptor-Mediated Immunity to the Pathogenesis Caused by the Human Respiratory Syncytial Virus
11. Ubol, Sukathida, and Scott B. Halstead. “How innate immune mechanisms contribute to antibody-enhanced viral infections.” Clin. Vaccine Immunol. 17.12 (2010): 1829-1835. https://cvi.asm.org/content/17/12/1829.long
12. Russell, Clark D., et al. “The human immune response to respiratory syncytial virus infection.” Clinical microbiology reviews 30.2 (2017): 481-502. https://cmr.asm.org/content/cmr/30/2/481.full.pdf
13. Collins, Peter L., and Barney S. Graham. “Viral and host factors in human respiratory syncytial virus pathogenesis.” Journal of virology 82.5 (2008): 2040-2055. https://jvi.asm.org/content/jvi/82/5/2040.full.pdf
14. Altamirano-Lagos, María José, et al. “Current Animal Models for Understanding the Pathology Caused by the Respiratory Syncytial Virus.” Frontiers in microbiology 10 (2019). Current Animal Models for Understanding the Pathology Caused by the Respiratory Syncytial Virus
15. IMpact-RSV Study Group. “Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants.” Pediatrics 102 (1998): 531-537.
https://www.quora.com/Whats-the-scientific-explanation-of-Novavaxs-under-trial-respiratory-syncytial-virus-RSV-vaccines-trial-results-reporting-that-infections-were-32-7-more-common-among-the-vaccinated-infants/answer/Tirumalai-Kamala