Influenza is tricky due to its mutations. Every time, it emerges anew. Therefore, it is very difficult to come up with an “antidote”, although “difficult” does not mean “impossible”.
Influenza is one of the most aggressive and unpredictable diseases that stands out among known infections due to
- Global prevalence;
- High contagiosity;
- Post-infection complications ranging from common ENT and respiratory system disorders (pneumonia, rhinitis, sinusitis, bronchitis, and otitis) to heart sac involvement (myocarditis or pericarditis), and brain inflammation (encephalitis, meningoencephalitis, and arachnoiditis);
- High mortality rate: according to the European Scientific Working Group on Influenza, during epidemics, the death rate associated with influenza proper or influenza complications may reach 870 per 100,000 population. It has been proved that following influenza and ARVI, myocardial infarction incidence rate, including lethal cases, increases. Following influenza, the lethality rate in COPD patients may reach 30% vs. 0.1% in healthy subjects (Meta-analysis data. Palache, Abraham Mozes; Tainijoki-Seyer, Julia. The Fifth ESWI Inf. Conference, 14-17 September 2014, Riga, Latvia).
Global reach
The history knows many flu pandemics that can be compared to worldwide disasters. The so-called Spanish flu pandemic of 1918 is considered the deadliest in history. Over the first 9 months of the pandemic, the Spanish flu virus spread all over the world. It was the first pandemic wave followed by two more waves. People were infected and died in Europe, the USA, Australia, and Africa. Over the first 18 months, an estimated 550 million people, or 29.5% of the world population, were infected. Overall, this large-scale disaster claimed 50 to 100 million human lives (estimates vary), or 2.7–5.3 % of the global population. Thus, the lethality rate of the infected subjects was estimated at 10–20 %. Apart from a high mortality rate, the Spanish flu had one more specific feature: many of those who fell victims to the flu were healthy people in the 20–40-year age bracket; at the same time, older people and children who had traditionally been major flu targets were less infectible.
In the 1930s, the first vaccines emerged that immunized people against influenza virus. But the flu pandemic history was not over. In 1957–1958, the Asian flu made its advent from the Far East to kill 70 thousand people in the USA alone. In 1968–1969, the Hong Kong flu became a key concern, with primarily the elderly and children infected and an estimated 34 thousand people killed.
Even though a hundred years have elapsed from the start of the Spanish flu epidemic, people are still dying of influenza. According to the World Health Organization (WHO), every year, seasonal flu epidemics result in 3–5 million of severe infection cases globally.
Children under 2 years, pregnant women, the elderly of 65+ years, and chronic disease patients remain most vulnerable for flu virus. With flu infection, even healthy people may develop functional impairments of nearly all body systems and organs, including the central nervous system, respiratory and circulatory systems, gastrointestinal tract, muscles, kidneys, endocrine, and immune systems. In terms of complications, children often present with otitis, and patients of all ages may develop bacterial pneumonia. Besides, fighting flu infection exhausts the immune system making it vulnerable for bacterial infections that in themselves are not considered flu complications, although may be severe (e.g., pneumonia).
Continuous and persistent struggle against influenza that was given a hefty boost in the 20th century due to the discovery of viruses is still underway. Despite scientific advances, emergence of new efficacious medications and treatment methods, this dangerous infection has not been completely eradicated so far. The virus’ high mutation rate presses scientists all over the world to continue searching for ways to improve the efficacy of vaccines currently on the market to further reduce the likelihood of developing influenza.
Since the flu pathogen has been discovered, scientists have been continuously searching for an improved formula capable to efficiently control variable vaccine viruses. Annual vaccination is considered the most reliable way of flu prevention. According to the WHO, annual vaccination of the risk groups reduces flu morbidity by 60 % overall[1].
According to the Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, in 1996–2017, the percentage of the citizens receiving annual flu vaccination in Russia increased from 0.2 % to 46.5 %; as a result, the flu morbidity in this country decreased 85.5-fold[2].
Presently, within the framework of the National Immunization Schedule, immunization covers children aged 6 months and older; secondary school students, grades 1—11; university and vocational school students; adults of specific professions and jobs (medical, educational, transportation, and utilities workers, etc.); and adults aged 60+. Since 2014, vaccination has been additionally indicated in pregnant women, persons subject to military service, and chronic disease patients.
Flu vaccine evolution
From monovalent to quadrivalent vaccines
As new knowledge on influenza and new technologies emerged, to boost vaccine efficacy, manufacturers gradually moved from monovalent vaccines protecting against one virus strain to trivalent and quadrivalent vaccines. Until recently, trivalent vaccines were authorized in Russia that contained three flu virus strains, i.e. two flu type A viruses (H1N1 and H3N2) and one type B viral cell line.
Since 2012, the WHO has recommended using quadrivalent vaccines for influenza prevention due to the growing prevalence of the second influenza type B viruses. This recommendation relates to preventive efficacy pressure on flu vaccination and consequently a reduction in the morbidity rate, economic losses, and enhancement of patient trust in annual vaccination. Such vaccines are in the national immunization schedules of 10 countries. In 2018, Russia launched the first quadrivalent flu vaccine.
From live virus to inactivated vaccines
Another evolutionary path for vaccines was a transfer from live to inactivated vaccines. State-of-the-art vaccines do not contain live (albeit attenuated) flu viruses capable of inducing mild influenza, but they do contain highly purified surface antigens of the virus. With an inactivated vaccine, antigens (proteins) only are administered into the human body for the immune system to study them and adequately respond in case it encounters infectious viruses. Such vaccines cannot induce a disease and are characterized by high immunogenicity and improved tolerability.
Safe efficacy
A serious issue is still a search for safe and efficacious adjuvants, i.e. substances capable of boosting the immune response with a lower antigen concentration per vaccine shot. Thus, one of the key principles in the development of any pharmaceutical product is identifying a minimum efficacious API dose. Such approach provides for reducing the likelihood of site responses. It is also applicable for manufacturing vaccines, with their composition and quality being regulated by the European Pharmacopoeia (EP) or relevant national pharmacopoeias. According to the EP, the stated amount of haemagglutinin antigen for each strain present in the vaccine is 15 µg per dose, unless clinical evidence supports the use of a different amount[3]. It was this principle that made the foundation for the Russian adjuvanted flu vaccines of Grippol® family.
World standards
Among the Russian flu vaccines, there is a broad line of inactivated vaccines manufactured by Petrovax. These vaccines stand out due to the presence of an azoximer bromide immunoadjuvant (Polyoxidonium) that improves their immunogenic properties at a reduced antigen dose.
Russia has long-standing (more than 20 years) successful practices of using local flu vaccines Grippol® and Grippol® plus. The vaccine production process including the adjuvant has withstood the tests of time and numerous studies. Over that period, the vaccines were used to immunize about 400 million people. A high efficacy of adjuvanted vaccines has been demonstrated, in particular, in post-approval epidemiology studies in Moscow Region[4], St. Petersburg[5][6] in more than 11,000 children and more than 6,900 adults. Besides, Grippol® plus has proved to be superior to foreign vaccines in specific post-approval studies[7],[8]. Due to its efficacy, quality, and high safety profile, Grippol® plus has been widely used in the Russian market, has a flawless 8-year application experience under the Russian National Immunization Schedule in children and pregnant women, and has been exported to the EAEU and Iran. Recently, the efficacy and safety of flu vaccines containing a reduced antigen dose and adjuvant Polyoxidonium has also been supported by a report drafted by FluConsult, an independent European bioscience consultancy company.
In September 2018, Grippol vaccine family increased to include Grippol® Quadrivalent, the first Russian 4-valent flu vaccine to protect against two flu type A viruses and two type B viral cell lines (Victoria and Yamagata). It is the most advanced flu vaccine in the world based on an antigen sparing technology, with a high preventive activity and safety.
A decrease in the body antigen load is achieved due to the use of Polyoxidonium (azoximer bromide), a water-soluble, biodegradable adjuvant that enhances the immune response to vaccination and provides for cutting the antigen load three-fold as compared to traditional technologies, i.e. for using hemagglutinin 20 µg instead 60 µg. The vaccine provides for an efficient antibody response supported by clinical evidence. Presently, only six countries, apart from Russia, manufacture quadrivalent vaccines on their own, including Australia, the USA, Canada, New Zealand, Germany, and France.
Grippol® Quadrivalent is indicated for vaccination of adults aged 18-60 years and children aged 6-17 years.
[1] http://www.who.int/influenza/vaccines/virus/recommendations/201502_qanda_vaccineeffectiveness.pdf
[2] О состоянии санитарно-эпидемиологического благополучия населения в Российской Федерации в 2017 году: Государственный доклад. — М.: Федеральная служба по надзору в сфере защиты прав потребителей и благополучия человека, 2018.—268 с., стр. 109-110
[3] European Medicines Agency, Guideline on Influenza vaccines: «...The stated amount of haemagglutinin antigen for each strain present in the vaccine is 15 µg per dose, unless clinical evidence supports the use of a different amount.»
[4] Ильина Т.Н. Оценка эпидемиологической эффективности гриппозной инактивированной полимер-субъединичной вакцины при иммунизации школьников. Вопросы современной педиатрии. 2009. т.8 № 5. С. 47-51.
[5] Ерофеева М.К., Никоноров И.Ю., Максакова В.Л., Ельшина Г.А. и др. Оценка эффективности применения гриппозной вакцины Гриппол® плюс у детей школьного возраста в период эпидемии гриппа 2008 — 2009 годов. Эпидемиология и Вакцинопрофилактика. 2010. № 4 (53). С. 80-86.
[6] Н.П. Шмелева, В.П. Шиманович, Н.В. Сивец и др. Оценка профилактической эффективности вакцины Гриппол® плюс при массовой вакцинации организованных взрослых и детских коллективов в Республике Беларусь. Эпидемиология и Вакцинопрофилактика. 2017; № 5(96): 33-42.
[7] А.А. Рулева, С.М. Харит, И.В. Фридман, Д.А. Лиознов и др. Результаты исследования по сравнительной оценке реактогенности и иммуногенности гриппозных инактивированных вакцин. МЕДИЦИНСКИЙ СОВЕТ. 2016; № 05: 47-51.
[8] С.М. Харит, Д.А. Лиознов, А.А. Рулева. Сравнительная оценка реактогенности и иммуногенности коммерческих гриппозных инактивированных вакцин: полимер-субъединичной Гриппол плюс, субъединичной Инфлювак, сплит-вакцины Ваксигрип. Эпидемиология и Вакцинопрофилактика. 2017. № 2 (93).
