In October 1979, more than 180 years after edward Jenner, the father of immunology, founded modern vaccinology, the World Health Organization (WHO) declared in Nairobi, Kenya, that "the world has eliminated smallpox." As one of the oldest infectious diseases, smallpox has plagued humans for at least 3,000 years. In the 20th century alone, the disease claimed the lives of 300 million people worldwide.
Edward Jenner, the father of immunology, contributed more by testing to prove that after vaccinia vaccination, subjects were artificially infected with smallpox virus but did not cause disease.
In May 2020, as another emerging infectious disease, COVID-19, was sweeping the world, WHO identified smallpox eradication as "a source of hope for the fight against COVID-19 and other diseases.". Dr Tedros Adhanom Ghebreyesus, WHO Director-General, said that humanity's victory over smallpox was a reminder that "the world was able to get rid of smallpox thanks to unprecedented solidarity and the availability of safe and effective vaccines." Unity plus science equals solutions! ”
"In the pre-vaccine era, the incidence and case fatality rate of infectious diseases were very high. A serious infectious disease may even change the course of a people, a country or even the entire history of mankind. Thomas Triomphe, executive vice president of the vaccine global business unit of French pharmaceutical giant Sanofi, sighed in an exclusive interview with the surging news (www.thepaper.cn) reporter, just imagine, without vaccines, how many children will not be able to reach adulthood? Without vaccines, what would the world look like today?
As the most serious public health threat since the 1918 H1N1 influenza pandemic, the COVID-19 pandemic has caused more than 500 million confirmed infections worldwide and reported more than 6 million deaths. How to view vaccines has also become a "compulsory course" for everyone for the first time.
1918 pandemic
Triomphe, who joined Sanofi in 2004, is a "veteran" in the field of vaccines. He was the global head of Sanofi's Influenza-Pneumonia Strategic Planning Department and was responsible for planning and designing a roadmap for the vaccine business, and as a father of three, he, like all other parents, was concerned about the threat of disease in his children.
"When my daughter was only a few months old, she was hospitalized for respiratory syncytial virus (RSV) and watched my child struggle to breathe, and I believe that no parent would want to face this feeling of helplessness." When it comes to nirsevimab, a long-acting monoclonal antibody that Sanofi and AstraZeneca are jointly developing to prevent respiratory syncytial virus infection in all infants, Triomphe has far more mixed feelings than purely commercial expectations.
He stressed that immunization to prevent infectious diseases and possible complications can help reduce the economic burden on a country's health system, such as the annual influenza season, influenza vaccines can keep people as far away from influenza as possible. In addition, having good immunization programmes allows countries to respond quickly to new outbreaks or pandemics in the best possible way.
However, whether it's Sanofi or other vaccine industry players around the world, there is always room for improvement. "A vaccine revolution began quietly before the COVID-19 outbreak, and covid-19 has accelerated that process." As the public has deeply felt, the new mRNA technology, which was still in the "budding" stage, has become a key technology in the "comprehensive vaccine development toolbox".
Triomphe believes that the emerging innovations in the field of vaccines will reshape the landscape of human health protection in the future.
Thomas Triomphe, Executive Vice President, Sanofi Vaccines Global Business Unit.
A vaccine revolution that preceded the COVID-19 outbreak has quietly begun
The last week of April is World Immunization Week, and this year's theme is "Long Life For All", which represents the opportunity for everyone to live a fulfilling life and the freedom to pursue the vision and ambition of happiness. It's not easy to realize this vision, "We know that only under the protection of vaccines can people focus on the future, and vaccines protect each of us from the burden of various diseases." Triomphe said.
In fact, for scientists, they usually have a natural motivation to seek out new science and technology to treat and prevent disease. Companies in the field of life and health are often founded by these scientists.
"For more than 100 years, we have developed vaccines that help people of all ages prevent disease and reduce the severity of infectious disease infections. We are constantly exploring the mechanisms behind infectious disease infections, designing specific vaccines for each pathogen to help humans defeat various infectious diseases. "Looking back at the history of Sanofi vaccines, we can see vaccine pioneers such as Louis Pasteur, John Fitzgerald, and Richard Sly.
Louis Pasteur, the founder of modern microbiology and the inventor of the rabies vaccine.
Talking about the role of vaccines in more than two centuries, Triomphe said that in the pre-vaccine era, the incidence and case fatality rates of infectious diseases were very high. A serious infectious disease may even change the course of a people, a country or even the entire history of mankind. In the age of vaccines, such threats are drastically reduced.
In addition to smallpox, he cites the example of polio, another infectious disease that promises to be eliminated, or polio, which has saved more than 18 million people from paralysis or death over the past 30 years. "We are working with the international community to eradicate polio. Over the past 20 years, more than 1.1 billion children worldwide have been immunized, saving as many as 3 million lives each year and helping to cut child mortality in half. ”
According to WHO data, polio is currently endemic only in afghanistan and Pakistan.
The boundaries of preventable diseases continue to expand in the 21st century, and for vaccine giants including Sanofi, "there is still a lot of room for improvement." Triomphe points out that a vaccine revolution has quietly begun before the COVID-19 outbreak, and the COVID-19 pandemic has accelerated the process.
This vaccine revolution includes that new technologies such as mRNA are adding new tools to our preventive medicine toolbox. Speaking about the "dark horse" of mRNA in the COVID-19 pandemic, Triomphe said that mRNA vaccines allow cells to directly produce "mimics" of viruses or bacteria, which will be recognized and activated by the immune system, so that the body can resist future real disease infections. "The DNA in human cells is like a masterpiece sheet music, the composition is very good, but it takes a conductor to convert it into beautiful music, and mRNA happens to be such a master conductor."
In the field of COVID-19 vaccines, Sanofi and GlaxoSmithKline have sought regulatory approval in Europe for the first generation of COVID-19 vaccines jointly developed by the two sides. Data from relevant studies show that it is a universal booster for all currently approved COVID-19 vaccine platforms to increase neutralizing antibody levels. The two companies will submit final applications to the U.S. FDA and other global regulators in the coming weeks.
Triomphe is also pleased to see mRNA technology applied to COVID-19 vaccines. "The technology that was already present before the COVID-19 pandemic is now a very timely and popular solution," he said. Against the backdrop of COVID-19, widespread attention and massive investment in mRNA technology has accelerated its success. ”
Triomphe also mentioned that mRNA technology is still in its infancy and needs to be further improved before it can be applied to conventional vaccination, "especially in terms of thermal stability and tolerability." ”
It is worth noting that in August 2021, Sanofi acquired Clinical-stage mRNA therapy company Translate Bio for a total of about $3.2 billion. In June 2018, Sanofi and Translate Bio entered into an R&D cooperation agreement to develop an mRNA vaccine; this agreement will be further expanded in 2020 to address a wide range of diseases that may occur now and in the future.
At the end of June 2021, Sanofi also created a new mRNA Vaccine Center of Excellence and announced that it will invest about 400 million euros per year. "This will not only accelerate the development of our mRNA vaccine portfolio, but also add to new vaccines developed using proven technologies." Triomphe believes that while mRNA technology cannot yet be a solution for all diseases, translating it into a conventional disease prevention tool could have a huge impact on many unmet public health needs.
"Today, it is a key new technology in our 'Arsenal of Integrated Vaccine Development' and promises to reshape health protection in the future." For Sanofi, mRNA technology will be developed in tandem with other existing platforms including inactivated vaccines, polysaccharide vaccines, recombinant vaccines, subunit vaccines, and viral vector vaccines.
Triomphe revealed that in terms of vaccine research and development, it is expected that by 2025, Sanofi will conduct human clinical trials for 10 candidate vaccines, 6 of which will use mRNA technology.
Principles of mRNA vaccines
Seek new vaccines that are first-of-its-kind or best-in-class
The innovation of the mRNA technology platform is one of the important development directions of new vaccine technology. From vaccine development and production to vaccination, Triomphe believes that new technologies run through the process, "technology is an effective way to achieve goals." ”
Which areas to aim for layout is itself an "innovative science". "We will prioritize new vaccine areas that can successfully bring first-of-its-kind or best-in-class vaccines to people around the world."
For Sanofi's vaccine business, influenza is an important layout area. According to the 2021 Sanofi financial report, the sales of the vaccine division last year were 6.323 billion euros, an increase of 6.8% compared with the same period in 2020, of which influenza vaccine sales reached a record level. "Every year, we provide more than 250 million doses of influenza vaccines worldwide, and influenza is an important area where we are accelerating the development of the next generation of vaccines."
It is reported that Sanofi will initiate clinical research on quadrivalent influenza mRNA vaccine candidates in 2022. "In the field of influenza mRNA vaccines, we always keep in mind that the tolerability and thermal stability of new influenza vaccines must be equal to or better than existing vaccines." Triomphe said that in the development of the next generation of influenza vaccines, Sanofi's goal is to provide products that are more effective than existing vaccines, which means that diseases other than influenza need to be protected and reduce the risk of other serious diseases after getting the flu, such as hospitalization due to myocardial infarction, pneumonia or stroke.
In fact, such a need is particularly urgent among the elderly over 60 years old. Overall, the elderly are the focus of influenza prevention, and such people have a weak immune system and are often accompanied by chronic diseases in addition to being susceptible to infection. Previous studies have shown that even in healthy adults, myocardial infarction after influenza infection is 10 times more likely than when there was no infection.
"Influenza vaccination is the best public health measure to prevent influenza and its complications, but studies have shown that traditional flu vaccines are less protective of older adults than other age groups because of their weaker immune systems." To that end, Sanofi has been developing and rolling out new flu vaccines for the past decade. "For example, we used a completely new recombinant technique to prepare a differentiated vaccine that better matches antigens to circulating strains." It is reported that compared with the standard dose of quadrivalent influenza vaccine, the antigen content of the recombinant quadrivalent influenza vaccine is 3 times that of the vaccine, and in people aged 50 years and older, the relative effectiveness of preventing PCR-confirmed influenza has increased by 30%, and the vaccine was approved in Hong Kong, China last April.
In China, 80% of the excess deaths in the respiratory tract caused by influenza are over 60 years old. Triomphe said, "More and more enhanced influenza vaccines are now being widely used globally, and they can better protect older people from influenza. ”
In addition to influenza, Sanofi is also deploying in new and unmet areas such as respiratory syncytial virus, acne, and chlamydial infections. Triomphe uses respiratory syncytial virus as an example to say that for more than 60 years, many vaccine manufacturers have been developing respiratory syncytial virus prevention methods, but there have been few breakthroughs.
Respiratory syncytial virus is the most common viral pathogen causing acute lower respiratory tract infections (LRTI) in infants and young children worldwide. It is also the leading cause of hospitalizations in all infants, with most PSV-related hospitalizations occurring in healthy infants born at term. In 2015, there were about 33 million new cases of lower respiratory tract infections associated with Zygocytic virus worldwide, resulting in hospitalizations for more than 3.2 million patients and the death of about 60,000 children under the age of 5.
The New England Journal of Medicine (NEJM) published a positive result evaluating the Phase 3 trial of nirsevimab.
In March, the leading medical journal The New England Journal of Medicine (NEJM) published positive results evaluating the Phase 3 trial of nirsevimab, a collaboration between Sanofi and AstraZeneca, and the first long-acting monoclonal antibody under development to provide respiratory syncytial virus preventive protection for all infants with just one dose.
The data showed that nirsevimab reduced the rate of treatment-needed LRTI (including hospitalization) due to respiratory syncytial virus by 74.5% compared to placebo. This data suggests that nirsevimab will hopefully provide safe and effective respiratory syncytial virus immunity protection for all infants, filling the gap in this area of virus prevention and control.
Nirsevimab has conducted clinical studies in more than 30 countries around the world and is listed in the accelerated development qualification of several authoritative regulatory agencies. Triomphe said, "In China, the prevention plan has not only been included in the breakthrough therapeutic drug program by the China Food and Drug Administration Review Center, but also a phase III clinical study for healthy infants in China has also been launched. "There are currently no drugs on the market in China that are effective in preventing and treating respiratory syncytial virus-related diseases.
Triomphe concludes that there are many factors that influence the success of vaccines during development, "but experience in pandemics has shown that when we prioritize disease prevention and continue to invest in innovation, we can always find solutions to major public health challenges." ”
Triomphe also cautions that in the context of the COVID-19 pandemic, we need to be wary of the risk of other infectious disease "immunization programs" or disruption.
He stressed that many infectious diseases with high basic immunization coverage were also highly contagious and pathogenic. Taking pertussis as an example, pertussis has been effectively controlled since the early 1970s when dtp.19 vaccine was widely used in clinical practice. "In recent years, due to factors such as insufficient vaccine immunization or untimely vaccination, differences in vaccination strategies, improvement of diagnostic standards and improvement of surveillance systems, many countries have seen the phenomenon of 'pertussis recurrence'. On the one hand, existing immunization strategies need to be improved, and on the other hand, once basic vaccines such as DTP are not vaccinated in time, children are put at risk of infection again. ”
In fact, during the peak of the new crown epidemic, most parts of the world have strict quarantine measures, and influenza is also at a low level. Triomphe believes that this also reduces the pre-existing immunity of the population, which may lay hidden dangers for a new round of influenza outbreaks, and then add up to the removal of social restrictions in many areas, which is more likely to trigger more serious influenza outbreaks in the future. "So it's crucial to get the flu vaccine before the annual flu festival."
It is worth noting that in addition to unmet disease areas and new technology platforms, Sanofi's vaccine innovation chain also extends to the EVF (Evolutive Vaccines Facilities) factory that is driving a revolution in vaccine production.
In a nutshell, EVFs use digitalization to empower vaccine production. "Designed to enable more agile and flexible manufacturing across multiple vaccines and biological platforms, including enzymes and monoclonal antibodies, and to minimize our impact on the environment." EVFs can produce multiple vaccine components simultaneously, either for a single vaccine or for more complex combination vaccines. Triomphe said that Sanofi invested 900 million euros in five years to build two EVF plants, one in Neville-sur-Saône in France and the other in Singapore, which are expected to be completed by the end of 2025 and the beginning of 2026, respectively.
Triomphe believes that EVF plants have more potential in accelerating capacity expansion and adapting to changes in global vaccine demand. For example, in the past, each vaccine factory would focus on a disease and build its own technology or process, it said. If you move from one vaccine to another, it usually takes several months to adjust. "It only takes about 12 days to get through the EVF plant."
Shortening the "time difference" of vaccines in the Chinese market
For any industry, the Chinese market cannot be ignored. This is no exception for Sanofi. According to Sanofi's 2021 financial report, China's revenue was 2.720 billion euros, an increase of 7.9% year-on-year.
This year also happens to be the 40th anniversary of Sanofi's entry into China, and from the perspective of immunization, "we have witnessed the gratifying changes in Immunization in China." "China has implemented the national immunization program since 1978, and in 2007 the national immunization program expanded its scope from "4 seedlings to 6 diseases" to "14 seedlings to prevent 15 diseases". These include hepatitis B vaccine, BCG vaccine, inactivated polio vaccine, live attenuated polio vaccine, DTP vaccine, etc.
In Triomphe's observation, on the one hand, the scope of China's immunization program is expanding; on the other hand, for diseases and vaccines that are not included in the immunization program, various parts of China are also exploring and trying, "for example, Beijing and Shenzhen municipality have been funded by local governments to receive free influenza vaccines for the elderly, primary and secondary school students since 2007 and 2017, respectively, and some cities have encouraged young women of appropriate age to get HPV vaccines." "These measures will effectively increase the vaccination rate of susceptible people and have a positive impact on the overall preventive protection of Chinese society."
"Sanofi sees China as one of the key strategic markets, and we will continue to bring cutting-edge disease prevention solutions to the Chinese public through multi-dimensional vaccine innovation initiatives." Triomphe said, "We hope to meet the diversified health needs of the Chinese people and shorten the vaccine 'time difference' by accelerating the introduction of innovative technologies and preventive means; in addition, we will continue to increase investment in China, promote the innovation and upgrading of vaccine full-link, and help the development of China's public health cause." ”
Compared with developed countries, the annual vaccination rate of influenza vaccine for the whole population in China is extremely low, less than 5%. Research by the Chinese Center for Disease Control and Prevention also shows that the influenza vaccination rate for the elderly over 60 years old is only 4.3%, and the medical staff is less than 15%. WHO's recommendation is that countries set a target of 75% for recommending influenza vaccination rates for the elderly population, and there is clearly a big gap in China.
Triomphe believes that there may be many reasons for China's low vaccination rate: for example, there is room for improvement in the adult vaccination service system, the traditional technical route vaccine production cycle is long, and the public has insufficient understanding of the harm of influenza and the value of vaccines.
Triomphe said that in the future, Sanofi's multi-dimensional vaccine innovation initiatives in the Chinese market include, first, efforts to accelerate the introduction of more innovative technologies and preventive measures. For example, it is expected to become the world's first immunoprophylaxis program that can be widely used in infants and young children to prevent respiratory syncytial virus infection, and the world's first approved recombinant quadrivalent influenza vaccine.
Second, promote China's public health capacity building. "Sanofi is also actively seeking cooperation with the Chinese Preventive Medicine Association, Peking University and other institutions to jointly explore new ideas for preventive immunization, further enhance the professional ability of medical personnel, help improve China's public health professional ability and system upgrade, and improve the detection capacity of respiratory infectious diseases."
Third, actively promote the full-link innovation of China's vaccine industry. "We continue to promote cooperation and innovation between production, learning, research and use, and work together to seek the best solution for vaccine innovation with a positive and innovative attitude." Triomphe, for example, includes working with partners to strengthen digital vaccine science and public education, explore innovative solutions for vaccination such as unmanned vaccination cabins, and help improve vaccine accessibility.
Fourth, we will continue to actively participate in the construction of the Guangdong-Hong Kong-Macao Greater Bay Area and promote the implementation of a number of innovative measures. This includes building a model of China's urban immunization planning strategy, building an international academic exchange platform in the field of high-standard vaccines, and continuing to build an international vaccine innovation center in the Greater Bay Area.
It is worth mentioning that on November 6, 2019, witnessed by the heads of state of China and France, the Shenzhen Municipal Government and Sanofi signed the Memorandum of Understanding on Strategic Cooperation in Vaccine Innovation at the Great Hall of the People in Beijing, and the two sides will give full play to their respective comparative advantages and jointly promote the strategic cooperation project on vaccine innovation. According to the memorandum of understanding, Sanofi plans to further increase investment in the next 10 years to promote its vaccine innovation projects, pilot vaccine government-enterprise cooperation mechanisms, create a model of China's urban immunization planning strategy, establish a vaccine innovation center, and create a high-level international vaccine summit forum.
Two years later, on December 4, 2021, the Greater Bay Area International Vaccine Innovation Center was inaugurated in Shenzhen. Triomphe said, "As China's first international vaccine innovation center, its birth is also a very innovative initiative at the global level, which has built a bridge between China and global vaccine innovation cooperation. ”
Triomphe commented that China's immunization program policy has achieved remarkable achievements, "the most direct evidence lies in the increase in life expectancy and the decline in the prevalence of various diseases." "From polio, which seriously threatens the health of Chinese children, to the prevention of diseases such as whooping cough and hepatitis B, "all of them support China's determination and overall standard of epidemic prevention." ”
"One point of prevention is better than ten points of treatment." The value of vaccines lies not only in the fact that it prevents a particular disease, but also in the positive, long-term impact it has on individuals, families, and society. Triomphe concluded.