Influenza vaccine

Subsequently colored TEM image of an influenza virus with membrane proteins (red), virus membrane (white), lumen (brown) and ribonucleoproteins (violet); in a split vaccine, the virus membrane is dissolved

An influenza vaccine (synonymous flu vaccine ) is a vaccine against the influenza virus . Influenza vaccines are used for flu vaccination (influenza vaccination).

properties

Influenza vaccines are purified antigens , split vaccines , inactivated viruses, or attenuated viruses . Due to the comparatively high genetic variability due to antigen shift and antigen drift (as mechanisms of immune evasion ) of the influenza viruses, the epitopes that are effective in a vaccine are often not present in the influenza viruses of the following season. As a result, the effectiveness of the approved influenza vaccines is limited to viruses similar to the vaccine strain and there is little immunity to other strains of influenza. Furthermore, the Paul Ehrlich Institute publishes current reference strains for seasonal influenza vaccines in Germany every year in accordance with the current recommendations of the World Health Organization and the Committee for Human Medicinal Products at the European Medicines Agency, on the basis of which the vaccine production is adapted. Due to the variability, these recommendations change almost every year for one or more strains. The reference strains include two influenza A viruses and one influenza B virus for common trivalent (trivalent) vaccines and a second influenza B virus for tetravalent (quadrivalent, tetravalent) vaccines. In contrast, pandemic influenza vaccines such as those against a highly pathogenic variant of the influenza A virus H5N1 , as the trigger of the avian flu H5N1 , or against the strain A / California / 7/2009 (H1N1) pdm09 of the influenza A virus H1N1 , as the trigger Pandemic H1N1 2009/10 , only one vaccine strain. Since the originally pandemic H1N1 virus strains have been circulating worldwide as seasonal flu since 2010 (with the usual variability), they have been among the reference strains for seasonal influenza vaccines since 2010. Influenza vaccines are on the World Health Organization's list of Essential Medicines .

immunology

Influenza vaccines produce neutralizing antibodies that prevent cells from re-infecting with the same strain of virus. To a small extent, these antibodies are cross-reactive with other influenza strains. The antibodies are mainly formed against the humoral immunodominant hemagglutinin and neuraminidase . These antibodies can be used in the course of a virological diagnosis to determine the titer in the vaccinated person or the vaccine serotype . Purified antigens, split or inactivated influenza vaccines are not absorbed into cells, which is why there is no pronounced cellular immune response .

Side effects

Adverse drug reactions from influenza vaccines include pain and swelling at the injection site and a day-long fever. The composition of the swine flu vaccine Pandemrix administered from 2009 to 2010 can presumably lead to narcolepsy in rare cases .

Manufacture of the vaccine

Genetic virus reassortment diagram in preparation for vaccine production

Culture media

The viruses for the flu vaccination are cultivated and multiplied in different media:

Chicken eggs

The virus is currently reproduced mainly in special incubated chicken eggs , the “specific pathogen free eggs”, which are 10–11 days old. In February of each year, the WHO decides on the composition of the seasonal winter vaccine. The so-called “seed virus” of the selected virus strains is sent to the manufacturer. In order to obtain optimal yields, the manufacturer carries out an HG (high-growth) reassortment . This takes about six weeks. The influenza virus multiplies in the Chorio - allantoic membrane. The eggs inoculated (inoculated) with the influenza virus are incubated for three days at 32 ° C. During this period, the virus multiplies very strongly. The eggs are opened and 6-7 ml of virus-containing allantoic fluid is harvested per egg. However, this type of production has disadvantages: The production of the vaccine takes about 6 months, the finished vaccine is available in June / July and is subjected to annual clinical studies. In the event of an influenza pandemic , large-scale egg production cannot be achieved due to the need for millions of eggs, as the planning of the logistical capacities required for this requires around 2 years in advance. In addition, egg vaccines require complicated purification and cause side effects, with egg protein allergies being a particular problem. Another shortcoming is the susceptibility of the production process to contamination and the necessary use of large quantities of antibiotics . Pandemic influenza strains are also very aggressive; In particular, strains of avian origin cannot be reproduced on chicken embryos.

Cell cultures

An alternative is to produce the vaccine in Vero cells . The advantages of this technology lie in the shortness of the production process (by eliminating the HG reassortment ) and the large production capacities. This enables a quick response to rapidly increasing demand. Vero cells are cultivated on an industrial scale in bioreactors with a capacity of several 1000 liters. Pandemic strains can be propagated with high yields. The sterile technology (technology from the point of view of the sterilisability and cleanability of the systems, as well as the retention capacity against microorganisms or biologically active substances) enables a safe design of the production facility. Dealing with pandemic influenza strains requires biological protection level 3 (BSL-3; Bio safety level), which cannot be achieved for egg facilities due to the process sequence (difficult to automate). The application made by the industry available flu vaccine just covers the average starting annual expected consumption, so the WHO on 19 August 2005 in the case of a renewed pandemic brought serious concerns about a looming shortage expressed.

Experimental procedure

Research is being carried out, for example, on the manufacture of the flu vaccine with the help of ciliates . The method should be faster and less risky than the previous standard.

Dead and live vaccines

Depending on the type of further vaccine preparation, a distinction is made between dead vaccines and live vaccines for influenza vaccines, as is the case with vaccines against other pathogens .

Dead vaccines

They are divided into:

• Inactivated whole particle vaccines (also: full virus vaccine): Inactivation (killing) of viruses by means of chemical substances / substance combinations, e.g. B. formaldehyde , beta-propiolactone and psoralen . The virus envelope is retained.
• (Inactivated) partial particle vaccines (also: split virus vaccine): Destruction (splitting) of the virus envelope with detergents or strong organic solvents. The viruses can also be inactivated (killed) with chemical substances.
• Subunit vaccines : the surface is completely dissolved and specific components ( hemagglutinin and neuraminidase proteins) are cleaned out. Another possibility is to produce the subunits recombinantly . Subunit vaccines are only slightly immunogenic , but have few side effects.

Live vaccines

In the production of live vaccines against influenza viruses, viruses are used that are attenuated but still able to reproduce ("vital"): ( English Live Attenuated Influenza Vaccine , LAIV , "living attenuated influenza vaccines"). A distinction is made here between

• Cold-adapted strains : these strains are only able to multiply at temperatures around 25 ° C, which limits the virus to the upper respiratory tract. Due to the lack of replication in the lower airways, only mild symptoms develop, not complete influenza. An example is the tribe A / Leningrad / 134/47/57 (H2N2)
• temperature-sensitive strains : the replication of these strains is limited to a temperature range of 38–39 ° C; here, too, the lower respiratory tract is not affected.

genetic techniques to generate a new virus subtype in preparation for vaccine manufacture

These vaccines are given intranasally . Their advantage over the previously used dead vaccines is that the vital viruses stimulate the immune system for longer and not only cause a humoral immune response , but also a cellular immune response . The disadvantage of influenza vaccines from pathogens that are still capable of reproducing is that the side effects are more frequent or more severe. The Swiss approval process for an attenuated influenza virus ( Nasaflu ) had to be canceled in 2001 due to paresis of the facial muscles. Therefore, attenuated influenza vaccines are not approved or recommended for pregnant women, people with a weakened immune system due to illness or under 2 or over 50 years of age.

Future influenza vaccines

The vaccines that have been approved to date target the bulges ("heads") of the hemagglutinin molecules on the surface of the virus. This molecule region changes in less than one influenza season due to antigen shift and antigen drift. This leads to fluctuating and on average only low effectiveness of the vaccines and the need to test them anew every year, to produce them in large quantities and to vaccinate them to all target persons. The health authorities of the USA and the European Union are therefore supporting the development of a “universal vaccine” against influenza, which, like the vaccines against almost all other pathogens, would only rarely need to be adjusted and re-vaccinated, but would be sufficiently effective over several seasons. One approach to this are vaccines that induce broadly neutralizing anti-IAV antibodies against the extracellular domain of matrix protein 2 (M2e) or against a certain area of hemagglutinin ( English stalk region , "stem region" between head and transmembrane domain ). Both the extracellular domain of M2 and the stem region of hemagglutinin are not very variable (highly conserved ) between the subtypes of influenza viruses . Therefore, a high selection pressure to preserve these amino acid sequences and their function is assumed, although the possibilities for immune evasion of the influenza viruses are limited as a result. Vaccines that attach to the stalk region of the hemagglutinin have been investigated on test subjects in Phase III since 2018 . Further approaches to increasing the broader effectiveness include the induction of cytotoxic T cells and T helper cells against conserved epitopes of several strains of the influenza viruses or their consensus sequence with the help of vectors , since cytotoxic T cells are only induced to a small extent by the split vaccines. Another approach is influenza vaccines made from messenger RNA , in the European Union for example supported by CORDIS and the UniVax project by institutions from seven EU countries. On the one hand, RNA vaccines are intended to ensure that the influenza virus no longer produces any reproductive offspring in the body of the vaccinated person. On the other hand, the immune system should be better prepared for future variants of the influenza virus.

WHO: recommended composition of vaccines since 1998/1999

For current recommendations, see flu vaccination

Northern hemisphere of the earth		Southern hemisphere of the earth
season	composition	season	composition
2020/2021	Chicken-based or live-attenuated influenza vaccines: A / Guangdong-Maonan / SWL1536 / 2019 (H1N1) pdm09-like strain A / Hong Kong / 2671/2019 (H3N2) -like strain B / Washington / 02/2019-like trunk (B / Victoria line) in the quadruple vaccine as a second B antigen: B / Phuket / 3073/2013 (B / Yamagata lineage) -like strain cell-based influenza vaccines: A / Hawaii / 70/2019 (H1N1) pdm09-like strain A / Hong Kong / 45/2019 (H3N2) -like strain B / Washington / 02/2019-like trunk (B / Victoria line) in the quadruple vaccine as a second B antigen: B / Phuket / 3073/2013-like strain (B / Yamagata lineage)	2021
2019/2020	A / Brisbane / 02/2018 (H1N1), pdm09-like strain A / Kansas / 14/2017 (H3N2) -like strain B / Colorado / 06/2017-like strain (B / Victoria / 2/87 line) in the quadruple vaccine also variant of B / Phuket / 3073/2013-like strain (B / Yamagata / 16/88 line)	2020	A / Brisbane / 02/2018 (H1N1) pdm09-like strain A / South Australia / 34/2019 (H3N2) -like strain B / Washington / 02/2019-like strain (B / Victoria line) in the quadruple vaccine also B / Phuket / 3073/2013-like strain (B / Yamagata line)
2018/2019	A / Michigan / 45/2015 (H1N1) pdm09-like A / Singapore / INFIMH-16-0019 / 2016 (H3N2) -like B / Colorado / 06/2017-like (B / Victoria / 2/87-line) in quadruple vaccine also B / Phuket / 3073/2013-like (B / Yamagata / 16/88 line)	2018	A / Michigan / 45/2015 (H1N1) pdm09 A / Singapore / INFIMH-16-0019 / 2016 (H3N2) B / Phuket / 3073/2013 in the quadruple vaccine also B / Brisbane / 60/2008
2017/2018	A / Michigan / 45/2015 (H1N1) pdm09 A / Hong Kong / 4801/2014 (H3N2) B / Brisbane / 60/2008 in the quadruple vaccine also B / Phuket / 3073/2013	2017	A / Michigan / 45/2015 (H1N1) pdm09 A / Hong Kong / 4801/2014 (H3N2) B / Brisbane / 60/2008 in the quadruple vaccine also B / Phuket / 3073/2013
2016/2017	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Hong Kong / 4801/2014 (H3N2) B / Brisbane / 60/2008 in the quadruple vaccine also B / Phuket / 3073/2013	2016	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Hong Kong / 4801/2014 (H3N2) B / Brisbane / 60/2008 in the quadruple vaccine also B / Phuket / 3073/2013
2015/2016	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Switzerland / 9715293/2013 (H3N2) B / Phuket / 3073/2013 in the quadruple vaccine also B / Brisbane / 60/2008	2015	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Switzerland / 9715293/2013 (H3N2) (three similar ones are named) B / Phuket / 3073/2013 in the quadruple vaccine also B / Brisbane / 60/2008
2014/2015	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Texas / 50/2012 (H3N2) B / Massachusetts / 2/2012	2014	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Texas / 50/2012 (H3N2) B / Massachusetts / 2/2012
2013/2014	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Victoria / 361/2011 (H3N2) B / Massachusetts / 2/2012	2013	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Victoria / 361/2011 (H3N2) B / Wisconsin / 1/2010
2012/2013	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Victoria / 361/2011 (H3N2) B / Wisconsin / 1/2010	2012	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Perth / 16/2009 (H3N2) B / Brisbane / 60/2008
2011/2012	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Perth / 16/2009 (H3N2) (strains like A / Wisconsin / 15/2009) B / Brisbane / 60/2008	2011	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Perth / 16/2009 (H3N2) B / Brisbane / 60/2008
2010/2011	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Perth / 16/2009 (H3N2) (strains like A / Wisconsin / 15/2009) B / Brisbane / 60/2008	2010	A / California / 7/2009 (H1N1) pdm09 (so-called "swine flu") A / Perth / 16/2009 (H3N2) B / Brisbane / 60/2008
2009/2010	A / Brisbane / 59/2007 (H1N1) A / Brisbane / 10/2007 (H3N2) B / Brisbane / 60/2008	2009	A / Brisbane / 59/2007 (H1N1) (strains like A / South Dakota / 6/2007) A / Brisbane / 10/2007 (H3N2) (like A / Brisbane / 10/2007 or A / Uruguay / 716/2007) B / Florida / 4/2006 (tribes like B / Brisbane / 3/2007)
2008/2009	A / Brisbane / 59/2007 (H1N1) A / Brisbane / 10/2007 (H3N2) B / Florida / 4/2006 (B / Brisbane / 3/2007)	2008	A / Solomon Islands / 3/2006 (H1N1) A / Brisbane / 10/2007 (H3N2) B / Florida / 4/2006
2007/2008	A / Solomon Islands / 3/2006 (H1N1) A / Wisconsin / 67/2005 (H3N2) (like A / Hiroshima / 52/2005) B / Malaysia / 2506/2004	2007	A / New Caledonia / 20/99 (H1N1) A / Wisconsin / 67/2005 (H3N2) B / Malaysia / 2506/2004
2006/2007	A / New Caledonia / 20/99 (H1N1) A / Wisconsin / 67/2005 (H3N2) (A / Wisconsin / 67/2005 or A / Hiroshima / 52/2005) B / Malaysia / 2506/2004 (like B / Ohio / 1/2005 or B / Victoria / 2/87)	2006	A / New Caledonia / 20/99 (H1N1) A / California / 7/2004 (H3N2) (also A / New York / 55/2004) B / Malaysia / 2506/2004
2005/2006	A / New Caledonia / 20/1999 (H1N1) A / California / 7/2004 (H3N2) (like A / New York / 55/2004) B / Jiangsu / 10/2003	2005	A / New Caledonia / 20/99 (H1N1) A / Wellington / 1/2004 (H3N2) B / Shanghai / 361/2002 (B / Shanghai / 361/2002, B / Jilin / 20/2003 or B / Jiangsu / 10 / 2003)
2004/2005	A / New Caledonia / 20/99 (H1N1) A / Fujian / 411/2002 (H3N2) (like A / Wyoming / 3/2003 or A / Kumamoto / 102/2002) B / Shanghai / 361/2002 (like the tribes B / Shanghai / 361/2002 or B / Jilin / 20/2003). Because of the widespread use, B / Jiangsu / 10/2003 strains were also used.	2004	A / New Caledonia / 20/99 (H1N1) A / Fujian / 411/2002 (H3N2) (A / Kumamoto / 102/2002 and A / Wyoming / 3/2003 were similar virus isolates grown in chicken eggs) B / Hong Kong / 330 / 2001 (B / Shandong / 7/97, ​​B / Hong Kong / 330/2001 and B / Hong Kong / 1434/2002; B / Brisbane / 32/2002 was also available)
2003/2004	A / New Caledonia / 20/99 (H1N1) A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) B / Hong Kong / 330/2001 (strains like B / Shandong / 7/97 , B / Hong Kong / 330/2001, B / Hong Kong / 1434/2002)	2003	A / New Caledonia / 20/99 (H1N1) A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) B / Hong Kong / 330/2001 (strains like B / Shandong / 7/97 , B / Hong Kong / 330/2001, B / Hong Kong / 1434/2002)
2002/2003	A / New Caledonia / 20/99 (H1N1) A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) B / Hong Kong / 330/2001	2002	A / New Caledonia / 20/99 (H1N1) A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) B / Sichuan / 379/99 (strains like B / Guangdong / 120/2000, B / Johannesburg / 5/99 or B / Victoria / 504/2000)
2001/2002	A / New Caledonia / 20/99 (H1N1) A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) B / Sichuan / 379/99 (strains like B / Johannesburg / 5/99 and B / Victoria / 504/2000)	2001	A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) A / New Caledonia / 20/99 (H1N1) B / Sichuan / 379/99 (strains like B / Guangdong / 120/2000, B / Johannesburg / 5/99 or B / Victoria / 504/2000)
2000/2001	A / Moscow / 10/99 (H3N2) (strains like A / Panama / 2007/99) A / New Caledonia / 20/99 (H1N1) B / Beijing / 184/93	2000	A / Moscow / 10/99 (H3N2) A / New Caledonia / 20/99 (H1N1) B / Beijing / 184/93 (strains like B / Shangdong / 7/97)
1999/2000	A / Sydney / 5/97 (H3N2) A / Beijing / 262/95 (H1N1) B / Beijing / 184/93 (tribes like B / Shangdong / 7/97)	1999	A / Sydney / 5/97 (H3N2) A / Beijing / 262/95 (H1N1) B / Beijing / 184/93 (vaccines such as B / Harbin / 7/94)
1998/1999	A / Sydney / 5/97 (H3N2) A / Beijing / 262/95 (H1N1) B / Beijing / 184/93 (vaccines such as B / Harbin / 7/94)	1998

Vaccines approved in Germany

For currently approved vaccines, see flu vaccination
season 2017/2018

vaccine	comment	Substance group	virulence	Minimum age of the vaccinated	Maximum age of the vaccinated	administration
Afluria 2017/2018		Split vaccine	inactivated	5	-	intramuscular
Begipal 2017/2018		Surface antigen subunit vaccine	inactivated	0.5	-	intramuscular
Fluad 2017/2018		Surface antigen subunit vaccine	inactivated	65	-	intramuscular
Fluarix		Split vaccine	inactivated	0.5	-	intramuscular
Fluenz Tetra 2017/2018	Influenza virus types A, H1N1 / A, H3N2 / B (Victoria lineage) / B (Yamagata lineage)	all	live attenuated	2	17th	nasal
Flu vaccine CSL		Split vaccine	inactivated	5	-	intramuscular
Influenza vaccine STADA N 2017/2018		Surface antigen subunit vaccine	inactivated	0.5	-	intramuscular
IDflu	Strength: 15 µg	Split vaccine	inactivated	60	-	intradermal
Influs split SSW		Split vaccine	inactivated	0.5	-	intramuscular
Influsplit Tetra 2017/2018		Split vaccine	inactivated	3	-	intramuscular
Influvac 2017/2018		Surface antigen subunit vaccine	inactivated	0.5	-	intramuscular
Influvac Tetra		Surface antigen subunit vaccine	inactivated	18th	-	intramuscularly or deep subcutaneously
INTANZA	Strength: 15 µg	Split vaccine	inactivated	60	-	intradermal
Optaflu	produced in cell culture	Surface antigen subunit vaccine	inactivated	18th	-	intramuscular
Vaxigrip 2017/2018		Split vaccine	inactivated	0.5	-	intramuscularly, if necessary deep subcutaneously
Vaxigrip Tetra 2017/2018		Split vaccine	inactivated	3	-	intramuscularly, if necessary deep subcutaneously
Xanaflu 2017/2018		Surface antigen subunit vaccine	inactivated	0.5	-	intramuscular
Xanaflu Tetra		Surface antigen subunit vaccine	inactivated	18th	-	intramuscularly or deep subcutaneously

For the 10 vaccines with the indication 2017/2018, the changes for the 2017/2018 season were already approved on August 24, 2017.

literature

• DM Knipe, Peter M. Howley , DE Griffin, (Eds.): Fields Virology. 5th edition. Lippincott Williams & Wilkins, Philadelphia 2007, ISBN 978-0-7817-6060-7 .

Individual evidence

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31. ↑ Recommended composition of influenza virus vaccines for use in the 2017 southern hemisphere influenza season .
32. ↑ Recommended composition of influenza virus vaccines for use in the 2016-2017 northern hemisphere influenza season .
33. ↑ Recommended composition of influenza virus vaccines for use in the 2016 southern hemisphere influenza season .
34. ↑ Recommended composition of influenza virus vaccines for use in the 2015-2016 northern hemisphere influenza season .
35. ↑ WHO - Recommended composition of influenza virus vaccines for use in the 2015 southern hemisphere influenza season .
36. ↑ WHO - Recommended composition of influenza virus vaccines for use in the 2014-2015 northern hemisphere influenza season .
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39. ↑ WHO - Recommended composition of influenza virus vaccines for use in the 2013 southern hemisphere influenza season .
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47. ↑ who.int ,
48. ↑ Centers for Disease Control and Prevention - Influenza (Flu) - Weekly Report: Influenza Summary Update 20, 2004-2005 Season .
49. ^ WHO - Recommendations for Influenza Vaccine Composition .
50. ↑ who.int (PDF; 217 kB)
51. ↑ who.int ,
52. ↑ Update: Influenza Activity - United States and Worldwide, 2003-04 Season, and Composition of the 2004-05 Influenza Vaccine .
53. ^ WHO - Recommendations for Influenza Vaccine Composition .
54. ↑ http://www.who.int/csr/disease/influenza/recommendations2004/en/index.html ( Memento from May 30, 2004 in the Internet Archive )
55. ^ WHO - Recommendations for Influenza Vaccine Composition .
56. ^ WHO - Recommendations for Influenza Vaccine Composition .
57. ^ WHO - Recommendations for Influenza Vaccine Composition .
58. ^ WHO - Recommendations for Influenza Vaccine Composition .
59. ^ WHO - Recommendations for Influenza Vaccine Composition .
60. ^ WHO - Recommendations for Influenza Vaccine Composition .
61. ^ WHO - Recommendations for Influenza Vaccine Composition .
62. ^ WHO - Recommendations for Influenza Vaccine Composition .
63. ^ WHO - Recommendations for Influenza Vaccine Composition .
64. ^ WHO - Recommendations for Influenza Vaccine Composition .
65. ^ WHO - Recommendations for Influenza Vaccine Composition .
66. ↑ Approved vaccines. ( Memento from June 26, 2019 in the Internet Archive ) PEI

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