Editing Vaccine (section)

==Production==
[[File:Preparation of measles vaccines.jpg|thumb| ]]

Vaccine production is fundamentally different from other kinds of manufacturing{{snd}}including regular [[pharmaceutical manufacturing]]{{snd}}in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy.<ref name="Plotkin_Page_45">{{cite book |last1=Gomez |first1=Phillip L. |last2=Robinson |first2=James M. |last3=Rogalewicz |first3=James |editor1-last=Plotkin |editor1-first=Stanley A. |editor2-last=Orenstein |editor2-first=Walter A. |editor3-last=Offit |editor3-first=Paul A. |title=Vaccines |date=2008 |publisher=Saunders Elsevier |location=New York |isbn=978-1-4377-2158-4 |pages=45–58 |edition=5th |chapter-url=https://books.google.com/books?id=ncxAHU67EoYC&pg=PT1 |access-date=26 March 2021 |chapter=Chapter 4: Vaccine Manufacturing |archive-date=18 April 2023 |archive-url=https://web.archive.org/web/20230418101022/https://books.google.com/books?id=ncxAHU67EoYC&pg=PT1 |url-status=live }}</ref> This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.<ref name="Plotkin_Page_45" />

Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, [[Cleanroom|clean rooms]], and containment rooms.<ref name="Plotkin_2017">{{cite journal |last1=Plotkin |first1=Stanley |last2=Robinson |first2=James M. |last3=Cunningham |first3=Gerard |last4=Iqbal |first4=Robyn |last5=Larsen |first5=Shannon |title=The complexity and cost of vaccine manufacturing – An overview |journal=Vaccine |date=24 July 2017 |volume=35 |issue=33 |pages=4064–4071 |doi=10.1016/j.vaccine.2017.06.003 |pmid=28647170 |pmc=5518734 }}</ref> There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines.<ref name="Plotkin_2017" /> With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.<ref name="Plotkin_2017" />

Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as [[Chicken as biological research model|chicken eggs]] (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for [[hepatitis A]]).<ref>{{Cite news|url = https://www.washingtonpost.com/wp-dyn/content/graphic/2009/11/24/GR2009112401834.html?sid=ST2009112401941|title = Three ways to make a vaccine|access-date = 5 August 2015|type = infographic|postscript = none|url-status=live|archive-url = https://web.archive.org/web/20151223231412/http://www.washingtonpost.com/wp-dyn/content/graphic/2009/11/24/GR2009112401834.html?sid=ST2009112401941|archive-date = 23 December 2015}}, in {{Cite news|url = https://www.washingtonpost.com/wp-dyn/content/story/2009/11/24/ST2009112401941.html?sid=ST2009112401941|title = Vaccine system remains antiquated|last = Stein|first = Rob|date = 24 November 2009|work = [[Wash. Post|The Washington Post]]|url-status=live|archive-url = https://web.archive.org/web/20171019084922/http://www.washingtonpost.com/wp-dyn/content/story/2009/11/24/ST2009112401941.html?sid=ST2009112401941|archive-date = 19 October 2017}}</ref> Bacteria are grown in [[bioreactor]]s (e.g., ''[[Haemophilus influenzae]]'' type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.<ref name=":0" /><ref name="WHOVaccSafety2" />

After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials.<ref name=":0">{{cite journal | vauthors = Muzumdar JM, Cline RR | title = Vaccine supply, demand, and policy: a primer | journal = Journal of the American Pharmacists Association | volume = 49 | issue = 4 | pages = e87–99 | year = 2009 | pmid = 19589753 | doi = 10.1331/JAPhA.2009.09007 | pmc = 7185851 }}</ref><ref name="WHOVaccSafety2">{{cite web |url=http://vaccine-safety-training.org/vaccine-components.html |title=Components of a vaccine |url-status=live |archive-url=https://web.archive.org/web/20170613192256/http://vaccine-safety-training.org/vaccine-components.html |archive-date=13 June 2017 }}</ref> Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.<ref name="Bae" />

The final stage in vaccine manufacture before distribution is [[fill and finish]], which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.<ref>{{cite web|date=6 April 2020|title=Vaccine Taskforce Aims|url=https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/893417/S0135_Vaccine_Taskforce_Aims.pdf|access-date=26 July 2020|website=assets.publishing.service.gov.uk|archive-date=26 July 2020|archive-url=https://web.archive.org/web/20200726102641/https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/893417/S0135_Vaccine_Taskforce_Aims.pdf|url-status=live}}</ref><ref>{{Cite journal|last1=Pagliusi|first1=Sonia|last2=Jarrett|first2=Stephen|last3=Hayman|first3=Benoit|last4=Kreysa|first4=Ulrike|last5=Prasad|first5=Sai D.|last6=Reers|first6=Martin|last7=Hong Thai|first7=Pham|last8=Wu|first8=Ke|last9=Zhang|first9=Youn Tao|last10=Baek|first10=Yeong Ok|last11=Kumar|first11=Anand|date=July 2020|title=Emerging manufacturers engagements in the COVID −19 vaccine research, development and supply|journal=Vaccine|volume=38|issue=34|pages=5418–5423|doi=10.1016/j.vaccine.2020.06.022|pmc=7287474|pmid=32600908}}</ref><ref>{{cite web|last1=Miller|first1=Joe|last2=Kuchler|first2=Hannah|date=28 April 2020|title=Drugmakers race to scale up vaccine capacity|url=https://www.ft.com/content/87d1170a-78bc-11ea-bd25-7fd923850377 |archive-url=https://ghostarchive.org/archive/20221210/https://www.ft.com/content/87d1170a-78bc-11ea-bd25-7fd923850377 |archive-date=10 December 2022 |url-access=subscription|access-date=26 July 2020|website=www.ft.com}}</ref>

Vaccine production techniques are evolving. Cultured [[mammalian cells]] are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using [[pathogen-associated molecular pattern]]s.<ref name=Bae>{{cite journal | vauthors = Bae K, Choi J, Jang Y, Ahn S, Hur B | title = Innovative vaccine production technologies: the evolution and value of vaccine production technologies | journal = Archives of Pharmacal Research | volume = 32 | issue = 4 | pages = 465–480 | date = April 2009 | pmid = 19407962 | doi = 10.1007/s12272-009-1400-1 | s2cid = 9066150 | doi-access = free }}</ref>

===Vaccine manufacturers===
The companies with the highest market share in vaccine production are [[Merck & Co.|Merck]], [[Sanofi]], [[GlaxoSmithKline]], [[Pfizer]] and [[Novartis]], with 70% of vaccine sales concentrated in the EU or US (2013).<ref name=plotkin2017>{{Cite book|title= Vaccines|first1= Stanley A. | last1=Plotkin| first2=Walter A. |last2 =Orenstein| first3= Paul A. |last3=Offit |first4=Kathryn M. |last4=Edwards |publisher=Elsevier |year=2017|isbn=978-0-323-39301-0}}</ref>{{rp|42}} Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.<ref name=plotkin2017/>{{rp|43}} Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.<ref name=plotkin2017/>{{rp|47}} The manufacturers in India are the most advanced in the developing world and include the [[Serum Institute of India]], one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a [[MRC-5]] cell culture instead of chicken eggs.<ref name=plotkin2017/>{{rp|48}} China's manufacturing capabilities are focused on supplying their own domestic need, with [[Sinopharm|Sinopharm (CNPGC)]] alone providing over 85% of the doses for 14 different vaccines in China.<ref name=plotkin2017/>{{rp|48}} Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.<ref name=plotkin2017/>{{rp|49}}