In May 2023, the Food and Drug Administration (FDA) approved a vaccine to prevent respiratory syncytial virus (RSV) infection, which many call the "first" approved RSV vaccine.
However, in fact, this vaccine is not the first approved RSV vaccine, and RSV vaccines have been approved before, but the RSV vaccine at that time did not really "prevent" the disease...
【"Mild" illness】
Respiratory syncytial virus is a negative single-stranded RNA virus with 10 genes encoding a total of 11 proteins [1], which is named from a membrane fusion protein on the surface of the virus called "F protein" that causes infected cells to fuse with neighboring cells to form "syncytial (multinucleated cells)", hence the name "syncytial virus" [2].
Among the viral genes, there are also two non-structural proteins that are very important, the "NS1" and "NS2" genes are non-structural promoter genes, and the two non-structural proteins NS1 and NS2 jointly inhibit "apoptosis" and "interferon response" [1].
Source: Nature Reviews Microbiology
RSV, like many respiratory viruses, is transmitted through respiratory secretions and can survive on surfaces for "hours" [3], causing infection and subsequent transmission by touching eyes, noses, or mouths after contaminating hands.
Symptomatic infection may present mild symptoms of upper respiratory tract infection (such as runny nose, sneezing, sore throat, cough, fever, etc.) and may lead to severe lower respiratory tract infection (pneumonia, etc.), among which "children" and "elderly" and "patients with underlying diseases" have a higher risk of severe disease after infection, and RSV is the most common cause of acute lower respiratory tract infection in infants and the leading cause of death in infants under one year of age [4].
Although most RSV infections are mild, their ability to coordinate "lethality" and "transmissibility" contributes to its global spread, resulting in approximately 64 million cases and approximately 160,000 deaths worldwide each year [5].
Among them, data show that it is estimated that 60,000~160,000 elderly people in the United States are hospitalized for RSV-induced lung infection every year, of which about 6,000~10,000 die from RSV infection5; Globally, 1.5 million RSV-associated acute respiratory infections in older adults occur annually in industrialized countries (where data are missing), with approximately 336,000 hospitalizations and 14,000 hospital deaths [6].
Faced with such a severe burden of disease, many scientific institutions are developing vaccines against RSV, and even began the development of related vaccines decades ago.
【"Failed" vaccines】
Respiratory syncytial virus was actually discovered in 1956, which also provided a good opportunity for humans to start vaccine development early.
However, it is interesting that at the beginning RSV was isolated from chimpanzees and named "chimpanzee coryza virus", and 1 year later American doctor and virologist Robert M. Robert M. Chanock isolated the virus in human pups (infants) with respiratory diseases [7]. It was later renamed "human orthopneumovirus" and "human respiratory syncytial virus".
Respiratory syncytial virus, source: PHIL CDC
After the virus was successfully isolated, in the context of the need for disease prevention and control and the discovery that the immune response obtained by natural infection did not provide good protection, resulting in "reinfection" being common [8], scientists started the development of RSV vaccine in full swing, and soon approved the first RSV vaccine - FI-RSV in 1960.
"FI-RSV" is an RSV whole virus inactivated vaccine prepared by classical formalin inactivation and enhanced immunogenicity by aluminum adjuvant. Studies have found that the vaccine is well tolerated and can be administered to children.
But unfortunately, the final result is not as ideal as many inactivated vaccines, and it can even be said that it is completely unworthy of being called a "vaccine"!
Infected babies hospitalized, source: self-expense
The vaccine was first approved for use in infants, but after the vaccine began to be officially used, it was found that many infants did not have a lower risk of disease after vaccination than unvaccinated infants, but in the winter vaccinated children developed more severe disease after being infected with RSV!
The data showed that 44% of children vaccinated with FI-RSV had severe or very severe pneumonia, compared with 5.6% of unvaccinated controls; Data from another center indicate that more than 80 percent of infants who have been vaccinated with FI-RSV require hospitalization after infection with RSV, compared with only 5 percent of infants who have not been vaccinated with FI-RSV, and two of the children die [8-10].
Afterwards, the researchers identified this as a "vaccine-associated enhanced respiratory disease (VAERD)" [11], possibly due to a delayed hypersensitivity/Arthus reaction, excessive production of non-neutralizing antibodies, complement deposition in the lungs, dysregulated Th2 immune response, and impaired T cell response [8,12].
Similar conditions have been found not only with inactivated vaccines, but also with purified F protein or vaccinia virus recombinant F protein vaccines since then [13].
Decades have passed, and no RSV vaccine has been declared successful.
【"Successful" innovation】
Although the hard lessons of RSV inactivated vaccines have had a negative impact on RSV vaccine development to some extent, the development of RSV vaccines has never stopped.
In this process, vaccines based on live viruses (attenuated, cold adaptation, etc.), cDNA (complementary DNA), viral vectors (pox virus, adenovirus, etc.), protein subunits (F protein, G protein - G protein is an attachment protein), synthetic peptides and other technology platforms have been tried, and then recombinant nanoparticles and mRNA vaccines have been developed [14-16].
Schematic diagram of respiratory virus vaccine, source: self-expense
At present, the three R&D institutions with the fastest approval and research progress in the world use the technologies are recombinant (based on better immunogenicity pre-conformation F glycoprotein) and mRNA (messenger RNA, antibody targeting F glycoprotein) two technologies, the three phase data of these three RSV vaccines are:
Monovalent F glycoprotein vaccine [17]: 82.6% protective efficacy against RSV-associated lower respiratory tract infections in ≥ 60-year-old adults (7 in the vaccine group and 40 in the placebo group); The protective efficacy against severe lung infections is 94.1%.
Bivalent F glycoprotein vaccine [18,19]: 66.7% protective efficacy against at least two or more signs and symptoms and 85.6% for at least three or more signs and symptoms in ≥ 60-year-old people after lower respiratory tract infection; The protective efficacy of infants with RSV-related severe lower respiratory tract disease within 90 days of birth after vaccination was 81.8% and 69.4% within 180 days of birth.
mRNA vaccine[20]: 83.7% protective efficacy against symptoms and signs of lower respiratory tract infection with 2 or more symptoms.
RSV infection diagnosis and treatment, source: self-pay purchase
On May 3, 2023, local time in the United States, the monovalent F glycoprotein vaccine was officially approved by the US Food and Drug Administration (FDA) for ≥ 60-year-old people, which also announced that the world has officially entered the era of RSV vaccines, and no longer can only deal with the virus invasion through expensive RSV-related antibody products.
Of course, although only the elderly are now approved to receive this monovalent F glycoprotein vaccine, children will soon be able to benefit from the vaccine as research advances.
【Q&A on "New Vaccines"】
Many frequently asked questions about the newly approved RSV vaccine are answered here:
1. Has China approved the RSV vaccine?
A: It was approved in the United States on May 3, 2023, but China has not yet approved the use of the vaccine, and many institutions in China are also developing RSV vaccines.
2. Who is this vaccine for?
A: It is suitable for ≥ 60-year-old elderly to prevent diseases caused by RSV infection, and it is expected that more age group groups will be approved for vaccination in the future with the cumulative research data.
3. How effective is this vaccine?
A: The protective efficacy against RSV-related lower respiratory tract infections was 82.6% (7 in the vaccine group and 40 in the placebo group); The protective efficacy against severe lung infections was 94.1% (1 in the vaccine group and 17 in the placebo group).
4. Why are vaccine figures so good?
A: Due to different clinical trial sites, we cannot determine which vaccine is more potent/effective, but since this vaccine uses AS01e adjuvant, the higher efficacy may be related to the high immunogenicity induced by this adjuvant.
Screenshot of the instruction manual, screenshot information source: FDA
5. How secure is it?
A: The overall safety profile is good, but one case of acute disseminated encephalomyelitis (with concurrent influenza vaccination) and one case of Guillain Barré syndrome have also been found in the study, and although no association with the vaccine has been established, more monitoring is required (it should be noted that there have also been 2 cases of Guillain syndrome with the bivalent F glycoprotein vaccine).
6. What are the adverse reactions?
A: The very common (≥10%) local adverse reactions were pain at the injection site (60.9%); Very common (≥10%) systemic adverse effects were fatigue (33.6%), myalgia (28.9%), headache (27.2%), and arthralgia (18.1%).
7. What is the estimated pricing?
A: It is unclear how much the vaccine will be priced, but according to previous EU studies[21], the reasonable pricing range is between €16.38 and €50.03.
If you have other questions, welcome to leave a message in the comment area.
Resources:
[1] Battles, Michael B., and Jason S. McLellan. "Respiratory syncytial virus entry and how to block it." Nature Reviews Microbiology 17.4 (2019): 233-245.
[2] Jha A, Jarvis H, Fraser C, Openshaw PJ (2016). Hui DS, Rossi GA, Johnston SL (eds.). Respiratory Syncytial Virus. SARS, MERS and other Viral Lung Infections. Wellcome Trust–Funded Monographs and Book Chapters. Sheffield (UK): European Respiratory Society. ISBN 978-1-84984-070-5. PMID 28742304
[3] Drysdale, Simon B et al. “Best practice in the prevention and management of paediatric respiratory syncytial virus infection.” Therapeutic advances in infectious disease vol. 3,2 (2016): 63-71. doi:10.1177/2049936116630243
[4] Griffiths, Cameron et al. “Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment.” Clinical microbiology reviews vol. 30,1 (2017): 277-319. doi:10.1128/CMR.00010-16
[5]“Respiratory Syncytial Virus (RSV).” National Institute of Allergy and Infectious Diseases, U.S. Department of Health and Human Services, https://www.niaid.nih.gov/diseases-conditions/respiratory-syncytial-virus-rsv#:~:text=RSV%20infection%20is%20estimated%20to,causes%20160%2C000%20deaths%20each%20year.
[6] Shi, Ting, et al. "Global disease burden estimates of respiratory syncytial virus–associated acute respiratory infection in older adults in 2015: a systematic review and meta-analysis." The Journal of infectious diseases 222.Supplement_7 (2020): S577-S583.
[7] Chanock, R. O. B. E. R. T., and B. E. R. N. A. R. D. Roizman. "Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). I. Isolation, properties and characterization." American journal of hygiene 66.3 (1957): 281-90.
[8] Mejias, Asuncion et al. “The journey to a respiratory syncytial virus vaccine.” Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology vol. 125,1 (2020): 36-46. doi:10.1016/j.anai.2020.03.017
[9] Gerretsen, Hannah E, and Charles J Sande. “Development of respiratory syncytial virus (RSV) vaccines for infants.” The Journal of infection vol. 74 Suppl 1,Suppl 1 (2017): S143-S146. doi:10.1016/S0163-4453(17)30205-0
[10] Murata, Yoshihiko. “Respiratory syncytial virus vaccine development.” Clinics in laboratory medicine vol. 29,4 (2009): 725-39. doi:10.1016/j.cll.2009.07.004
[11] CHIN, JAMES, et al. "Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population." American journal of epidemiology 89.4 (1969): 449-463.
[12] Polack, Fernando P., et al. "Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody." Nature medicine 5.6 (1999): 629-634.
[13] Bembridge, G P et al. “Recombinant vaccinia virus coexpressing the F protein of respiratory syncytial virus (RSV) and interleukin-4 (IL-4) does not inhibit the development of RSV-specific memory cytotoxic T lymphocytes, whereas priming is diminished in the presence of high levels of IL-2 or gamma interferon.” Journal of virology vol. 72,5 (1998): 4080-7. doi:10.1128/JVI.72.5.4080-4087.1998
[14] Dudas, R A, and R A Karron. “Respiratory syncytial virus vaccines.” Clinical microbiology reviews vol. 11,3 (1998): 430-9. doi:10.1128/CMR.11.3.430
[15] Mejias, Asuncion, et al. "Respiratory syncytial virus vaccines: are we making progress?." The Pediatric infectious disease journal 38.10 (2019): e266.
[16] Qiu, Xirui et al. “Development of mRNA vaccines against respiratory syncytial virus (RSV).” Cytokine & growth factor reviews vol. 68 (2022): 37-53. doi:10.1016/j.cytogfr.2022.10.001
[17] Papi, Alberto, et al. "Respiratory syncytial virus prefusion F protein vaccine in older adults." New England Journal of Medicine 388.7 (2023): 595-608.
[18] Walsh, Edward E., et al. "Efficacy and safety of a bivalent RSV prefusion F vaccine in older adults." New England Journal of Medicine (2023).
[19] Kampmann, Beate, et al. "Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants." New England Journal of Medicine (2023).
[20] Carvalho, Thiago. "mRNA vaccine effective against RSV respiratory disease." Nature Medicine (2023).
[21] Zeevat, F et al. “Exploratory Analysis of the Economically Justifiable Price of a Hypothetical RSV Vaccine for Older Adults in the Netherlands and the United Kingdom.” The Journal of infectious diseases vol. 226,Suppl 1 (2022): S102-S109. doi:10.1093/infdis/jiab118