As flu season approaches, how should we get vaccinated?

Produced by: Science Popularization China

Author: Fu Lifeng (Associate Researcher, Institute of Microbiology, Chinese Academy of Sciences) Xu Chang (Master Candidate, Institute of Microbiology, Chinese Academy of Sciences)

Producer: China Science Expo

Autumn is here, the temperature starts to drop, and it is the season when colds are more likely to occur.

Influenza virus is one of the common pathogens that cause colds. From the data of the National Influenza Center's weekly influenza monitoring report (Figures 1 and 2), it can be seen that both northern and southern China will enter the peak period of influenza infection.

Figure 1. Influenza-like illnesses reported by sentinel hospitals in northern provinces, 2021-2025 (%)

(Image source: National Influenza Center Influenza Surveillance Weekly Report No. 822)

Figure 2. Influenza-like illnesses reported by sentinel hospitals in southern provinces, 2021-2025 (%)

(Image source: National Influenza Center Influenza Surveillance Weekly Report No. 822)

What are the symptoms of influenza infection?

Influenza infection mainly presents with fever, headache, myalgia and general discomfort. The body temperature can reach 39 ~ 40℃, and there may be chills and chills. It is often accompanied by systemic symptoms such as muscle and joint pain, fatigue, and loss of appetite. There is often sore throat and dry cough. There may be nasal congestion, runny nose, discomfort behind the sternum, facial flushing, and conjunctival congestion.

Most influenza patients will recover within 1 week of symptom onset. Some influenza patients (especially young children, the elderly, pregnant women, or patients with certain underlying diseases) may develop influenza-related respiratory and neurological complications, and in severe cases, death.

Complications of the respiratory system include pneumonia ("white lung") and acute bronchitis, and can even induce asthma attacks. Among the complications of the nervous system, encephalitis and encephalopathy are the most common, among which acute necrotizing encephalopathy is classified as a critical case and is one of the important causes of death in children with influenza in my country.

What should we do?

An effective way to prevent influenza and reduce the burden of influenza-related severe illness and death is to get vaccinated.

What types of flu vaccines are available?

To explain the classification of influenza vaccines, we must first understand the classification of influenza viruses. The two main influenza viruses prevalent in the human population are type A and type B. Type A influenza viruses include H1N1 and H3N2, and type B influenza viruses include Yamagata (BY) and Victoria (BV) strains.

Vaccines are divided into trivalent influenza vaccines and quadrivalent influenza vaccines. The quadrivalent influenza vaccine includes all four virus subtypes mentioned above, that is, it can resist the four influenza viruses H1N1, H3N2, BY and BV. The trivalent influenza vaccine mainly targets H1N1, H3N2 and Victoria (BV). Among them, the reason why the trivalent vaccine does not include the Yamagata (BY) virus is based on the monitoring results of the WHO Global Influenza Surveillance and Response System (that is, the network of national influenza centers and WHO collaborating centers around the world). Since the outbreak of the new crown epidemic in 2020, there has been basically no BY epidemic in the world. Therefore, the current trivalent influenza vaccine does not include the BY virus.

According to the different methods of vaccine preparation, influenza vaccines can also be divided into inactivated influenza vaccines, split influenza vaccines, subunit influenza vaccines and live attenuated influenza vaccines.

Figure 3. Development history of influenza virus vaccines

(Image source: drawn by the author)

With so many types of vaccines, which one is the most effective?

1. Inactivated influenza vaccine

The inactivated influenza vaccine contains complete influenza virus particles, and the proportion of adverse reactions in the population after vaccination is higher than that of other vaccines. Therefore, my country has not currently approved the use of this vaccine.

The earliest inactivated influenza vaccines were prepared by using chicken embryos, which are fertilized eggs produced by healthy chickens, to breed influenza viruses, and then inactivating the viruses with formalin or formaldehyde.

2. Influenza split vaccine (injection)

In order to reduce adverse reactions, researchers inactivated the influenza virus propagated in chicken embryos with formaldehyde and then used a suitable lysing agent (such as Triton X-100) to split the lipid membrane structure of the influenza virus to expose the internal components of the virus. The purpose of this is to make the virus components in the vaccine purer and reduce other components that may cause adverse reactions.

After lysis, researchers will use a process called ultrafiltration centrifugation to remove the lysis agent, other impurity proteins and viral nucleic acid, retaining only the key parts of the virus, such as influenza virus hemagglutinin (HA) protein, neuraminidase (NA) protein, and part of the nucleoprotein (NP) and matrix protein (M). The vaccine prepared in this way is called an influenza split vaccine.

**The advantage of the influenza split vaccine is that it removes most of the virus components, so compared with the inactivated influenza vaccine, the influenza split vaccine has fewer adverse reactions and is safer. **At the same time, it retains the key proteins of the virus, which can stimulate the human body to produce an immune response, so the immunogenicity is also better, which can effectively help the human body build up defenses against the influenza virus.

Figure 4. R&D process of influenza subunit vaccines

(Image source: drawn by the author)

Influenza subunit vaccine (injection)

On the basis of the split vaccine, the researchers further removed the nucleoprotein and matrix protein of the influenza virus through sucrose density gradient centrifugation and molecular sieve separation, leaving only two proteins: hemagglutinin and neuraminidase on the surface of the influenza virus as antigens. The vaccine prepared in this way is the influenza subunit vaccine.

The influenza subunit vaccine has a more complex production process and higher purity than the influenza split vaccine, so it is more expensive, safer and has fewer adverse reactions.

Figure 5. R&D process of influenza subunit vaccines

(Image source: drawn by the author)

4. Live attenuated influenza vaccine (nasal spray)

The development of live attenuated influenza vaccines relies on two master donor virus strains (MDV): influenza A virus strain A/Ann Arbor/6/60 (H2N2) (Note: This naming method refers to [type/isolation location/strain number/isolation year (subtype)]) and influenza B virus strain B/Ann Arbor/1/66.

The genes of the main donor virus strain determine three characteristics of the live attenuated influenza vaccine: virulence attenuation (limiting its reactogenicity and pathogenicity), temperature sensitivity (limiting its replication in the lower respiratory tract), and cold adaptability (allowing it to replicate in the nasopharynx).

That is to say, this influenza live attenuated vaccine only replicates in the nasal mucosa at a lower temperature (31-33°C), thereby producing mucosal immunity, and hardly replicates in areas around 37°C (such as the lungs). Moreover, the nasal attenuated influenza live vaccine can stimulate the human body's triple immune response. In addition to effectively resisting the vaccine strain virus, it can also produce cross-immunity to other subtypes of influenza virus.

Figure 6. Schematic diagram of gene reassortment of live attenuated influenza vaccine

(Image source: drawn by the author)

The flu is different every year, so why can vaccines be developed in advance?

Every year, the World Health Organization (WHO) monitors and predicts upcoming influenza viruses: by analyzing influenza virus samples from around the world, it selects the strains most likely to circulate in the next season.

Readers who are interested in the components of this year's influenza vaccine can go to the official website of the World Health Organization to see their announcement of "Recommended Influenza Vaccine Composition for the 2024-2025 Northern Hemisphere Influenza Season".

Figure: WHO announces recommended influenza vaccine components for the 2024-2025 northern hemisphere influenza season

(Photo source: WHO official website)

For influenza split vaccines and influenza subunit vaccines, researchers selected influenza virus strains that are identical or similar to those predicted by the WHO as virus seeds for vaccine production.

For the live attenuated influenza vaccine, after obtaining this prediction information, researchers will use a technique called "classical reassortment" to recombinant a portion of the genes of the main donor virus strain (MDV) and two key gene fragments (hemagglutinin HA and neuraminidase NA) of the influenza virus predicted to be prevalent. In this way, a new vaccine can be produced that contains the key features of the influenza virus that is most likely to be prevalent that year.

So, even though the flu virus is different every year, through monitoring by the World Health Organization and advance preparation by researchers, vaccines can be developed in advance to prepare for the upcoming flu season.

When is the best time to get the flu vaccine?

Although each person's response to vaccination varies, research shows that:

The body's antibodies can reach protective levels 2-4 weeks after vaccination with influenza split vaccine and subunit vaccine. The vaccine-induced antibody level reaches a peak after 1 month and begins to decline after about 3 months. The protective effect can generally last for 6-8 months. Therefore, it is generally recommended to complete the vaccination before the end of October.

IgA antibodies can be produced as early as 3 days after vaccination with live attenuated influenza vaccine. In addition, for children aged 6 months to 8 years: 2 doses of influenza vaccine are required for the first time, with an interval of ≥ 4 weeks; if they have been vaccinated before, only 1 dose is required; children aged 9 years and above and adults: 1 dose per year.

In the future, a universal flu vaccine is expected to be available

In addition to the three influenza vaccines that have been marketed in China, namely influenza split vaccine, influenza subunit vaccine and live attenuated influenza vaccine, there are currently many other influenza vaccines based on new technologies under development, such as influenza recombinant subunit vaccine, influenza mRNA vaccine, influenza virus vaccine based on reverse genetics or gene editing technology, etc. The development of universal influenza vaccine is the main trend at present. In other words, in the future, we may be able to vaccinate against any influenza strain that infects humans. Looking forward to that day!

References:

1. National Influenza Center Influenza Surveillance Weekly Report No. 822

2. Technical Guidelines for Influenza Vaccination in China (2023-2024)

3. Nasal spray influenza live attenuated vaccine and human natural immune biological products circle

4. Next-generation live attenuated influenza vaccine platform biologics circle

5. Medical experts talk about influenza | Shu Yuelong: Innovation continues, influenza vaccine research progress Xinhuanet

6. Professor Qian Suyun: Interpretation of influenza-related encephalopathy in children - a complication that cannot be ignored