**: Yakudu Daily
Original: Huang Zhongping
This year's respiratory diseases are extremely rampant, influenza has been widespread twice at the beginning of the year and the end of the year, Mycoplasma pneumoniae has been raging since the first half of the year, from children to **, tens of millions of people have been attacked, and the demand for vaccines for respiratory diseases is becoming more and more intense. Fortunately, in 2023, after 60 years of hard work, a major breakthrough in the field of respiratory syncytial virus (RSV) vaccines has been achieved, and the two approved RSV vaccines have achieved shocking results in a short period of time due to an extremely unmet need.
Looking forward to 2024, the two approved RSV vaccines will continue to kill all sides and are expected to enter the ranks of the best-selling vaccines, and many RSV vaccines under development are also expected to make phased progress.
The first year of commercialization
2023 is known as the "first year of commercialization of RSV vaccines".
On May 3, GlaxoSmithKline (GSK)'s RSV vaccine AREXVY was approved by the US FDA for the prevention of lower respiratory tract diseases caused by RSV infection in the elderly population, which is the world's first RSV vaccine approved for marketing.
On May 31, Pfizer announced that its bivalent RSV vaccine, Abrysvo, was approved by the US FDA for the prevention of lower respiratory tract diseases caused by RSV in people aged 60 years and olderOn August 21, the FDA approved the ABRYSVO extension for pregnant women at 32-36 weeks gestation to prevent lower respiratory tract disease caused by the RSV virus in infants born to 6 months of age.
RSV vaccines have been commercialized worldwide.
*: Guoxin**Research Report.
Demand for RSV vaccines is so short of supply that the sales figures for RSV vaccines are astonishing.
In the first three quarters of this year, GSK's Arexvy sales reached 70.9 billion pounds, Pfizer's ABRYSVO sales reached 3$7.5 billion. You know, this is just the achievement of these two vaccines in more than a quarter on the market.
* sales data like a stimulant instantly ignited the enthusiasm of the market.
According to Yaodu statistics, there are nearly 70 RSV vaccines under development in the world, and in addition to GSK and Pfizer, foreign MNC giants have entered the market, including Johnson & Johnson, Sanofi, AstraZeneca, Merck, etc., and domestic companies including Advexin and Zhifei Biotechnology have layouts.
However, the progress of foreign and domestic R&D is obviously not in the same dimension.
Stars of the future
Failure is the mother of success, and we should not forget the "shoulders of giants" in addition to the successful development of RSV vaccines.
As early as the 60s of the last century, Pfizer took the lead in the research and development of RSV vaccines. At that time, it was a common method to use *** to inactivate the virus and then prepare it into a vaccine, and the RSV vaccine FI-RSV developed by Pfizer also adopted this technical route.
But unexpectedly, even the use of inactivated RSV virus has caused great harm to humans. In clinical trials, the FI-RSV vaccine not only failed to prevent children from being infected with the RSV virus, but instead led to the exacerbation of respiratory diseases after natural infection with RSV. In this trial, 16 of the 20 vaccinated children required hospitalization** and two children died. As a result, the development of RSV vaccines has stalled for decades.
Nov**ax's two failures are a suffrage, and Nov**ax nearly went bankrupt as a result.
In September 2016, the RSV F vaccine, the core pipeline of NOV**AX targeting respiratory syncytial virus (RSV) in the elderly, was declared a failure. The RSV F vaccine has entered Phase III clinical trials, with the primary goal of validating the efficacy of preventing moderate-severe RSV-associated lower respiratory tract disease and the secondary goal of validating the ability to reduce all respiratory diseases caused by RSV, but ultimately neither of these endpoints was met by RSV F.
February 2019,NOV**AX has once again announced another of its modelsRSV vaccineresvaxGlobal Phase III clinical study failed. Clinical results showed that resvaxFailedEnables the baby to reach within 3 months of lifePrevention of RSV lower respiratory tract infections (LRTIs).The primary endpoint.
Resvax pre-fusogenic F design and BLI detection data for neutralization of different epitope antibodies.
*: Guoxin**Research Report.
In addition to the AREXVY vaccine, GSK has previously developed two RSV vaccines, GSK3389245A and GSK3888550A. gsk3389245ais an adenovirus vaccine for infants and young children, but GSK stopped clinical research in 2021;gsk3888550ais an unadjuvanted recombinant protein vaccine primarily used for immunization in pregnant women, but in early 2022, based on the observations of routine safety evaluations by an independent data monitoring committee, GSK announced the suspension of enrollment and vaccination of its Phase III GRACE trial for maternal immunization, as well as the suspension of two other clinical trials in pregnant women.
B**Arian Nordic's RSV vaccine productmva-bn rsvThe R&D failure was announced in July 2023, which attracted great attention in China, mainly due to the introduction of the rights to the MVA-BN RSV vaccine by the domestic pharmaceutical company UniRay in March 2022. In phase III clinical studies of MVA-BN RSV, the efficacy in preventing the occurrence of at least two LRTD symptoms was only 429%, with no significant difference from placebo.
vac18193（jnj-64400141）It is an RSV vaccine developed by Johnson & Johnson based on the AD26 adenovirus vector platform, which was granted breakthrough designation by the US FDA in 2019. The vaccine leverages the unique characteristics of the new viral vector platform to package transgenes expressing the RSV viral fusion protein in adenovirus vectors, and to increase vaccine efficacy by applying human adenovirus 26 and 35 vectors (AD26 and AD35) to express the F protein. However, in March 2023, Johnson & Johnson abruptly announced its decision to withdraw from the RSV vaccine program and terminate the ongoing Phase III clinical Evergreen study.
Results of Phase II efficacy trial of VAC18193 vaccine.
*: Shenwan Hongyuan Research Report.
Stepping on the shoulders of the above "giants", RSV vaccines from different companies with different technical routes have shown a situation of "a hundred flowers blooming". In view of the characteristics of different susceptible populations and immunized targets, researchers have designed a variety of RSV vaccine types, including live attenuated vaccines, vectored vaccines, subunit vaccines, and particulate vaccines.
Subunit vaccines
The subunit vaccine is suitable for pregnant women and the elderly who have been infected with RSV, and is composed of RSV protein with immunogenicity, mostly using F protein, and a few using G protein or SH protein, with fewer antigenic components, and can not be replicated in the body, generally speaking, the immunogenicity is poor, and adjuvant or multiple vaccinations must be added to induce a sustained immune response. Due to its high safety profile and relative simplicity of preparation, the subunit vaccine is currently the most studied type of RSV vaccine, representing the Pfizer vaccinersvpref, GSK developmentrsvpref3and developed by the domestic pharmaceutical company Advexinadv110
Arexvy and RSVPrif have become global No. 1 respectively.
One or two RSV vaccines approved for marketing.
adv110 by:AdvecinIt is a potential RSV protein subunit vaccine candidate with novel adjuvants designed to protect children aged 6 months to 5 years and the elderly over 65 years of age, and is currently in Phase II clinical trials. Clinical data showed that after adv110 vaccination, the geometric mean concentration (GMC) of antigen-specific antibodies increased in all groups compared to the baseline level before immunization, and the response rate in all groups exceeded 80%, and the high-dose ADV110 (20) was given compared with the low-dose ADV110 (10 g) two-dose immunization group g) In the two immunization groups, antibodies could continue to be produced in the follow-up observation period, showing a stronger immune response and were statistically significant, and the additional third booster immunization would induce a further increase in antibody levels, and the level of antibody production at all observation time points was significantly higher than the initial baseline measurementsIn terms of safety, different doses of ADV110 vaccine showed good safety and tolerability.
ADV110 BARS13 mechanism of action.
*: Guoxin**Research Report.
mRNA vaccines
The great success of mRNA technology in the application of new crown vaccines means that mRNA has finally gone through the road of medicine in the field of conventional vaccines. Representatives of the field of RSV vaccines are Modernamrna-1345
mRNA-1345, developed by Moderna, is a monovalent mRNA RSV vaccine encoding the RSV pre-fusion F glycoprotein that uses the same lipid nanoparticles (LNPs) as Moderna's COVID-19 vaccine, containing optimized protein and codon sequences.
In January 2023, Moderna announced that the Phase ConquerRSV trial of mRNA-1345 in adults over 60 years of age met the primary endpoint of the number of cases of RSV-related lower respiratory tract disease (RSV-LRTD). A total of 22 countries were enrolled in this clinical trial, and nearly 3In 60,000 people over 60 years of age, the interim analysis showed that mRNA-1345 had a protective rate of 83 against two or more RSV-LRTD symptoms7%, with a protective efficacy of 82 against 3 or more RSV-LRTD symptoms4%, and the protective efficacy against acute respiratory diseases is 684%。
In July 2023, Moderna announced that it had submitted a global marketing application for mRNA-1345, including a marketing application to the European Union, Switzerland, and Australia, as well as a rolling marketing application to the U.S. FDA.
How Moderna's RSV vaccine works.
*: Guoxin**Research Report.
Live attenuated vaccines
The live attenuated vaccine is immunized by nasal drops, and the vaccine strain replicates in the upper respiratory tract, is not affected by maternal antibodies, and can activate mucosal immunity, block RSV infection, and is suitable for neonatal immunization. Represents the development of the vaccine under development for Sanofisp0125, Meissamv-012-968
SP0125 is a live attenuated vaccine developed by Sanofi and the first RSV vaccine designed to protect all young children. According to the Phase 1 2 data of SP0125, SP0125 is similar to placebo in terms of safety;In terms of vaccine response, the vaccine response to SP0125 was strong (93%) after two uses of the high-dose formulation, and there was a marginal difference between the low-dose and high-dose formulations. At present, SP0125 has entered Phase II clinical trial.
MV-012-968 is a product developed by Meissa VaccinesIntranasal, unadjuvant, live-attenuated vaccines designed to protect infants from RSV infection。In phase I clinical trials, the vaccine was well tolerated, highly attenuated, and elicited a strong RSV-specific mucosal IgA response in both ** and young children. Currently, MV-012-968 is in pediatric Phase I clinical trial and adult Phase II clinical trial.
Vector vaccines
Vector vaccines have the advantage of being highly effective in activating host innate and adaptive immunity. At present, commonly used vectors include viral vectors such as alphavirus, adenovirus, modified vaccinia Ankara virus (MVA), Newcastle disease virus, Sendai virus, and parainfluenza virusBacterial vectors such as recombinant BCG, Salmonella and Streptococcus grugini. The representative vaccines are Johnson & Johnson's adenovirus vector vaccine JNJ-64400141, and MVA-BN RSV jointly developed by B**arian Nordic and Yourui Pharmaceutical.
Unfortunately, as mentioned above, the development of JNJ-64400141 and MVA-BN RSV has been discontinued.
Particulate vaccines
Particulate vaccines include virus-like particle (VLP) vaccines, virus-like particle vaccines, and nanoparticle vaccines. VLP is a non-replicating, non-infectious, self-packaged particle composed of viral proteins, which has the advantage of being highly effective in activating adaptive and innate immunity in the absence of adjuvants. Nanoparticle vaccines use nanotechnology to display a definite number of subunit antigens with corresponding spatial conformation on the surface of nanospheres, mimicking host-virus surface interactions, activating the immune system and preventing viral infection. The representative vaccines are Resvax, developed by NOV**AX, and IVX-121, which is developed by LCOS**AX.
Resvax is unfortunately out.
New data results from an early clinical trial of IVX-121 show that:A sustained immune response was shown at six months post-vaccination, and the geometric mean titer (GMT) of antibodies to RSV-A in older adults was maintained at 64% to 98% of the GMT at day 28 post-vaccination at day 180 post-vaccination。In addition, IVX-121 continued to be well tolerated during the six-month follow-up, with no safety concerns observed.
Global RSV vaccine pipeline progress (based on technology pathways).
*: Guoxin**Research Report.
In China, there are at least 13 companies that have deployed RSV vaccine candidates. Among them, Advexin is in the clinical stage, and other vaccine companies such as Zhifei Biologics, Walvax Biologics, Blue Magpie Biologics, CSPC Pharmaceutical Group, etc., are all in the preclinical research stage.
Progress in the research and development of RSV vaccines in domestic enterprises.
*: Anxin** official website.
Conclusion
In terms of progress, we regret to see that the RSV vaccine is still in the early clinical stage in China, which means that it will take a long time for the RSV vaccine to land in the Chinese market, and it will still not be possible to wait for the RSV vaccine in 2024. However, catalyzed by the best performance, more and more pharmaceutical companies will invest in the research and development of RSV vaccines, and various technical routes are also expected to achieve phased victories in 2024, especially the expected mRNA technology. Where the heart desires, there will be repercussions. What is the follow-up development, Yaodu will continue to pay attention.
References
1. Official websites and annual reports of major listed companies.
2. "From the Verge of Bankruptcy to a Market Value of $26 Billion, the Apocalypse of the Rise of NOV**AX", Amino Observation, June 10, 2022
3. "The RSV vaccine introduced by Yourui Pharma has failed in overseas clinical trials, and many have failed in this technical route", Yicai, 2023-7-25
4. "Johnson & Johnson Terminates Phase III RSV Vaccine Project, Giving Way to Pfizer and GlaxoSmithKline", Pengbai News, March 30, 2023
5. "Tens of billions of RSV vaccine tracks, who will be happy and who will be worried?"., Gloria Medicine, March 13, 2023