06 June 2017

Vaccine with an additive

Cerium oxide increases the effectiveness of flu vaccines

Vladimir Ivanov, Corresponding Member of the Russian Academy of Sciences,
Nadezhda Zholobak, Candidate of Biological Sciences,
Alexander Shcherbakov, Candidate of Chemical Sciences.
Kommersant Nauka No. 1, February 2017.
Published on the website "Elements".

A standard industrial influenza vaccine modified with cerium dioxide increases the body's immune response to influenza viruses several times, both subtype A and subtype B, without causing side effects.

Flu epidemics sweep the globe every year. They have become so familiar that in the case of influenza, the term "pandemic", that is, a worldwide epidemic, has lost its original meaning. Now influenza pandemics are called only epidemics caused by particularly dangerous modifications of the virus ("Spanish", "Hong Kong", "bird", "pig" ...). This year is no exception, we are on the threshold of an ordinary, habitual pandemic, while by all signs it does not promise abnormally high mortality.

The flu virus is so labile that it is not possible to get rid of it completely, it is constantly changing, ahead of the latest flu medications and influenza vaccines. They are also constantly being improved, and sooner or later universal drugs and vaccines will solve the problem of influenza, and its large-scale epidemics will stop. The use of modern nanotechnology in the manufacture of vaccines is a promising breakthrough in this race.

How to treat the flu

When a person has already got the flu, he is treated with drugs that kill the flu virus. This is, as doctors say, etiotropic therapy, that is, treatment aimed at eliminating the cause (etio in Greek - "cause", tropos – "turn, direction").

Etiotropic substances include substances capable of damaging (inactivating) specific components of the influenza virus, as a rule, on its surface, in the virus envelope (Fig. 1, A). These drugs are especially effective in the early stages of the infectious process, when viruses in the patient's body have just begun to multiply.

Despite the extensive arsenal of chemotherapy drugs that suppress the reproduction of influenza viruses, they do not always effectively protect against influenza. And this is natural, because the use of etiotropic agents acting on any particular link in the process of virus reproduction is accompanied by the selection of virus strains resistant to such effects. As a result, after one season of using highly specific drugs, the detection rate of strains resistant to them ranges from 5 to 40%.

A more promising way is to prevent influenza and its severe consequences through vaccination. The introduction of the vaccine into the body causes an immune response: the body produces antibodies to surface antigens (hemagglutinin and neuraminidase) and other structural components of the virus (Fig. B). Vaccination actually provokes our body to manufacture its own "medicines" against the influenza virus.

How do medications act on the flu virus (A) and vaccines (B):


Arbidol interacts with hemagglutinin (surface protein) of influenza viruses, slowing down the release of viral nucleic acid and the reproduction of the virus. Relenza (zanamivir) and tamiflu (oseltamivir) inhibit the function of the viral enzyme neuraminidase in influenza A or B viruses, hindering the release of new viral particles from cells and their further spread in the body.
Rimantadine and amantadine block the action of the M2 protein, which plays a key role in the early stages of viral infection reproduction and affects the infectivity of newly synthesized influenza A viruses.
Amben, trasilol and other protease inhibitors prevent the activation of hemagglutinin and the initiation of the infectious process.
The introduction of the vaccine into the body (B) causes an immune response: the body produces antibodies to surface antigens (hemagglutinin and neuraminidase) and other structural components of the virus, that is, the vaccine provokes the body to manufacture its own "medicines" against the influenza virus.

Pros and cons of vaccines

Today, quite a lot of flu vaccines have been developed, all of them are divided into four types according to the method of their creation.

Positive qualities of the vaccine (the ability to form immunity to the virus) they are united by the concept of "immunogenicity". Negative (adverse reactions after immunization) – the concept of "reactogenicity". The ratio of these indicators determines the quality of the vaccine (efficacy and safety).

How flu vaccines are designed

An influenza vaccine may contain virions (whole viral particles) or fragments of virions of one (monovalent) or several (polyvalent) subtypes of the virus. As a rule, during the epidemic season, not one strain of the virus circulates, but several, therefore, complex vaccines have been developed and are used, which contain antigens to all strains expected in the current season.


Whole inactivated viruses are present in the whole virion vaccine. Its use causes a good immune response, but is accompanied by a large number of adverse reactions (especially in young children). Split, or split vaccines, contain destroyed inactivated virions of the influenza virus.
The composition of such vaccines includes all virion proteins: not only surface, but also internal antigens. The immunogenicity of whole-virion and split vaccines is almost the same, but the reactogenicity of the latter is lower. It is polyvalent split vaccines, for example, Vaxigrip / Fluzone or Fluarix, that are used most massively today. The latest developments are virosomal vaccines, for example, ultrix.
They are constructed by combining viral subunits into "virosomes" – virus-like nanoparticles. Virosomal vaccines are characterized by low reactogenicity and high immunogenicity, they are usually recommended for immunization of children and the elderly. Subunit vaccines (influvac, grippol, agrippal) are the least reactogenic, consisting only of the two most important anti-influenza surface viral proteins for the induction of the immune response: hemagglutinin and neuraminidase.
But such vaccines are also the least effective.

Unfortunately, these properties – immunogenicity and reactogenicity – are interrelated: the higher the effectiveness of the vaccine, the higher the risk of side effects on the body, and this is typical for all vaccines, regardless of their type, whether it is live inactivated, split or subunit; polyvalent (usually trivalent – against two seasonal strains of influenza A and one strain of influenza B) or pandemic (against a specific strain with increased virulence, for example, swine flu).

It is clear that the efforts of scientists are aimed at creating vaccines with maximum immunogenicity and minimum reactogenicity. To do this, the world's leading laboratories are investigating various types of viral material and methods of its processing, including the use of auxiliary additives.

Economics of Vaccine Viability

According to a report by the World Health Organization (WHO) Global Vaccine Market Features & Trends, the volume of the global influenza vaccine market has exceeded $3 billion, and in 2018 will reach $3.8 billion. Despite the crises, the growth of this market has been stable for the last 20 years. There are three main reasons for this.

Firstly, according to the same WHO, every year from 10 to 20% of the world's population suffers from influenza, and due to the high variability of influenza viruses, the incidence is unlikely to decrease in the foreseeable future.

Secondly, the pure market costs of vaccine manufacturers are relatively small, since in most developed countries, including In Russia, with a strict seasonal national calendar of preventive vaccinations (NCPP), up to 90% of vaccines are sold by state order. According to IMS Health, in the Russian Federation up to 83% are purchases according to the national calendar, 12% are regional purchases, 5% are the commercial market (retail). This year, it is planned to spend about 4 billion rubles on the purchase of influenza vaccines and vaccinations within the framework of the NCPP.

And finally, thirdly, most vaccines have a fairly long life, only the strains of influenza viruses against which vaccines are adapted change annually, and the capital costs of developing and implementing their production technology and clinical trials are already in the past.

Give me supplements!

As auxiliary substances, the vaccine may include preservatives, buffer components and immune response enhancers (so-called adjuvants). An example of adjuvants can be oil emulsions, globules of lipopolysaccharides, nanoparticles of inorganic substances, polymers or their combinations. For example, Sanofi Pasteur (manufacturer of the Vaxigrip vaccine) has recently patented a composition containing aluminum hydroxide nanoparticles stabilized with polyacrylate. It is known that fullerene derivatives and noble metal nanoparticles are used as adjuvants.

Adjuvants enhance immunogenicity, but they themselves can cause adverse reactions. In other words, existing adjuvants increase the reactogenicity of vaccines. Recently, the term ASIA (Autoimmune / Inflammatory Syndrome Induced by Adjuvants) has even appeared – an autoimmune inflammatory syndrome caused by adjuvants. The most common manifestations of this syndrome are fever, joint pain, dermatosis, weakness and muscle pain.

Structural adjustment of vaccines

Our research team modified the influenza vaccine with cerium dioxide nanoparticles. One of the key properties of nanocrystalline cerium dioxide particles is their ability to inactivate reactive oxygen species and prevent oxidative stress. And this made it possible to consider it as a safe adjuvant that does not cause ASIA.

Cerium is an element that opens a number of lanthanides (rare earths). It was opened in 1803 simultaneously in Sweden and Germany. It is named after the dwarf planet Ceres (and that is in honor of the Roman goddess of fertility). Cerium is the most common on Earth and the least expensive of the rare earth elements. Cerium has two interesting physical properties (they are not unique, but extremely rare and both were first discovered in cerium). One of them is an isostructural phase transition. At room temperature and a pressure of about 8000 atmospheres (this is not much for a physical laboratory), the volume of the crystal lattice decreases abruptly, but its geometry does not change.
The second property is the ability of cerium to accept two fairly stable oxidation states in compounds – +3 and +4, which distinguishes it from other lanthanides. Due to its properties, cerium is easy to separate from other rare earth metals, which makes it possible to widely use cerium compounds in industry, as part of abrasives, catalysts, pyrophoric alloys, etc. (For the possibilities of using cerium dioxide to protect against sunburn, see Kommersant-Nauka No. 3 of April 21, 2015.)

As a basis, we took the trivalent split vaccine Vaxigrip (Sanofi Pasteur, France), which includes inactivated split viruses A/H1N1 and A/H3N2, as well as the influenza B virus. The vaccine was modified by adding cerium dioxide nanoparticles 2-6 nm in size. The study of the immunogenicity of such a modified vaccine was carried out on white mongrel mice. Specialists can see the details of our work in the March 2016 issue of the international journal Antiviral Research, and here we will focus on practical results.

In animals immunized with an unmodified vaccine, there was a fourfold increase in the level of antibodies to influenza A/H1N1 and A/H3N2 viruses, but in the case of influenza B, the level of antibodies did not differ from unvaccinated animals. Thus, if the immunogenicity of the Vaxigrip vaccine to influenza A viruses meets the requirements of the European Committee for Influenza vaccines, then it does not for influenza B virus.

But in a group of mice receiving a vaccine modified with nanoparticles, there was a significant increase in antibody titers to all three varieties of influenza virus that are part of the vaccine. An eight–fold increase in the level of antibodies to influenza A/H1N1 and A/H3N2 viruses was detected, and to influenza B viruses (for which its low immunogenicity is a byword) – four times!


Modification of the vaccine by cerium dioxide nanoparticles leads to the formation of larger chimeric (composite) virus-like particles, which causes additional activation of the cross-immune response Modification of the vaccine with nanoparticles did not lead to an increase in its reactogenicity, but increased the duration of antibody circulation in the blood of immunized animals, which should provide longer protection against influenza.

The role of CeO 2 nanoparticles is visible if you look at the vaccine modified by them in an electron microscope. The usual Vaxigrip split vaccine is an unordered set of virus fragments. The introduction of cerium dioxide nanoparticles into its composition leads to the adsorption of the latter on viral membranes and the formation of larger particles containing fragments of various viruses. According to experiments, with such a structure of the vaccine, its effect is more effective.


A – model of interaction between viral membranes and cerium dioxide nanoparticles;  B – micrograph of the Vaxigrip vaccine after interaction with cerium dioxide nanoparticles

The developed method of vaccine modification is simple and economical, does not require fundamental technological changes in their production. To obtain a modified vaccine, it is enough to introduce cerium dioxide nanoparticles into its composition in a certain ratio, and then the fragments of viruses themselves are organized into multicomponent structures.

The method, of course, requires further in-depth study. But it is already clear that the use of cerium dioxide–based nanoconstructions in vaccines is a promising way to increase the specific activity of influenza vaccines.

Portal "Eternal youth" http://vechnayamolodost.ru  06.06.2017

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