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Embryonic chicken cells are commonly used in vaccine production. The viruses are grown in chicken eggs, or in embryonic cells taken from those eggs, and then inactivated or attenuated to produce the vaccine. But why can human viruses—some of which are not known to infect adult chickens—infect immature embryonic chicken cells?

For instance, according to this WHO fact sheet (https://www.who.int/news-room/fact-sheets/detail/measles), "Measles is a human disease and is not known to occur in animals." Yet the the measles virus prepared for the MMR vaccine is grown in chicken embryonic fibroblast cells.

N.B.: According to http://www.ogrod.uw.edu.pl/__data/assets/pdf_file/0010/2161/13a.pdf, while measles may have evolved from domestic animals, it is thought to have its origin in cattle rather than chickens: "Measles, for example, is closely related to two other morbilliviruses-canine distemper and rinderpest (a disease of cattle)" [1]

One guess is that, while a virus would normally require interaction with a species-specific surface protein to initiate membrane fusion (see https://www.frontiersin.org/articles/10.3389/fmicb.2011.00247/full [2]), and thus viral (or viral RNA) entry into the cell, the naive nature of undifferentiated chicken egg cells enables such fusion to occur without such species-specific proteins.

Another guess (in the opposite direction) is that the species-specificity of viral infection depends on species-specific cell recognition factors, and because the cells in chicken eggs are undifferentiated, or minimally differentiated, they possess a broad range of recognition factors (where the non-chicken-specific ones are lost as the cells differentiate).

It was surprisingly difficult to find information online about this. According to the the following (https://www.jstor.org/stable/30105172?seq=1), chicken embryo cells do become more resistant to viruses as the embryo ages; but this doesn't explain the lack of species-specificity:

"Cells dispersed from young embryos were permissive to viral growth, while those from older embryos were restrictive in an age-related pattern similar to that observed in ovo. The mechanism of natural antiviral cellular resistance did not involve viral attachment or release from cells from older embryos, but apparently depended on intracellular events during viral replication. These observations suggest that increasing natural resistance is based partially on intrinsic cellular changes. Sensitivity of a given virus and responsiveness of cells to the action of interferon may be more important to antiviral resistance than the amount of interferon that the virus induces." [3]

[1] Dobson, Andrew P., and E. Robin Carper. "Infectious diseases and human population history." Bioscience 46.2 (1996): 115-126.

[2] Hashiguchi, Takao, Katsumi Maenaka, and Yusuke Yanagi. "Measles virus hemagglutinin: structural insights into cell entry and measles vaccine." Frontiers in microbiology 2 (2011): 247.

[3] Morahan, Page S., and Sidney E. Grossberg. "Age-related cellular resistance of the chicken embryo to viral infections. I. Interferon and natural resistance to myxoviruses and vesicular stomatitis virus." The Journal of Infectious Diseases (1970): 615-623.

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    $\begingroup$ Flu viruses are not adapted to only infect humans. In fact a lot of wild species of it show up in birds (ducks and chicken) first, before they jump to humans. $\endgroup$ – Chris Oct 3 '20 at 6:45
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    $\begingroup$ @Chris Yes, some human viruses grown in eggs are also avian. That's why I was careful to write, in the first paragraph, "some of which [emphasis added] may not infect adult chickens". However the point, and the source of my question, is that eggs can be used to grow human viruses regardless of whether they can infect adult chickens or not. For instance, eggs are used to grow the measles virus for the MMR vaccine, and measles is not known to affect animals (besides us). [continued next comment] $\endgroup$ – theorist Oct 3 '20 at 8:03
  • $\begingroup$ [continuing....] Thus the fact that some of the viruses grown in eggs may also happen to infect adult chickens doesn't logically affect my question, which is: What allows the eggs to be infectable, independent of whether the adult chicken is susceptible or not? $\endgroup$ – theorist Oct 3 '20 at 8:03
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    $\begingroup$ I would suggest focusing on a single viral pathogen of humans and providing references showing that that virus doesn't affect adult chickens. Alternatively, can you provide references that support your assertion that human-affecting non-influenza viruses are typically grown in eggs? I did a quick search and found two sources saying that MMR is typically produced using viruses grown in chicken embryonic fibroblast cell cultures (or human cell lines) not eggs. $\endgroup$ – tyersome Oct 3 '20 at 18:17
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    $\begingroup$ @tyersome I've made it explict in my title and intro that the essence of my questions is not why viruses that can't infect the adult of the species can be grown in their eggs, but rather why they can be grown from immature, embryonic cells (irrespective of whether this is done in situ within the egg, or in such cells taken from the egg and grown in culture) . I've also given measles as an explicit example, since a WHO fact sheet (who.int/news-room/fact-sheets/detail/measles) says "Measles is a human disease and is not known to occur in animals." If I am able, I will post a primary reference. $\endgroup$ – theorist Oct 4 '20 at 2:37
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The measles vaccine uses an attenuated virus: one that has been modified to reduce virulence such that it is (hopefully) no longer harmful to the host but still retains the antigenic determinants to induce acquired immunity. Although in modern times rational attenuation by genetic engineering is becoming established [1], the traditional method involves simply growing the virus under conditions abnormal for it such that it must evolve to survive. This often involves culturing the virus in cell types (or possibly organisms) in which it does not typically cause infection. Due to existing variation within the viral population or novel mutations, the virus may, over time, adapt to infect these cells with some degree of efficiency. Importantly in the context of vaccine development, the genetic changes generated during this adaptation may also reduce the pathogens ability to causes disease in the host organism [2].

This effect was originally observed by Louis Pasteur in 19th century who subsequently used it to develop a vaccine against the bacterium Erysipelothrix rhusiopathiae, which infects pigs [3]. Pasteur noticed that propagating this bacterium in rabbits, in which it did not initially cause disease, increased its pathogenicity in rabbits while at the same time reduced its pathogenicity in pigs. The virus had evolved and this attenuated form was used as a vaccine in pigs.

The attenuated virus for measles vaccine was created by the same principle in the 1950s to 1960s. An isolate of the measles virus from an infected patient was successively passaged through human kidney cells, human amnion cells, fertilized hen's eggs [4] and chick embryonic cells [5]. This attenuated virus, which was now replicative in chick embryonic cells, was no longer infective in humans and was used as the basis of the measles vaccine [6].


References

[1] Bull JJ. 2015. Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it? Virus Evol 1(1):vev005

[2] Badget MR, Auer A, Carmichael LE, Parrish CR, Bull JJ. 2002. Evolutionary Dynamics of Viral Attenuation. J Virol 76(20):10524–10529

[3] Bazin H. 2003. A brief history of the prevention of infectious diseases by immunisations. Comp Immunol Microbiol Infect Dis 26(5-6):293-308

[4] Milovanovic MV, Enders JF, Mitus A. 1957. Cultivation of Measles Virus in Human Amnion Cells and in Developing Chick Embryo. Exp Biol Med 95(1):120-127

[5] Katz SL, Milovanovic MV, Enders JF. 1958. Propagation of Measles Virus in Cultures of Chick Embryo Cells. Exp Biol Med 97(1):23-29

[6] Enders JF, Katz SL, Milovanovic MV, Holloway A. 1960. Studies on an Attenuated Measles-Virus Vaccine — Development and Preparation of the Vaccine: Technics for Assay of Effects of Vaccination. N Engl J Med 263:153-159

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  • $\begingroup$ Thanks for the very informative post. I wasn't aware of the "passaging" technique in vaccine development. I'll need some time to look over the references before I reply in more detail. But my initial read of your post is that viruses grown in immature cells of species the viruses don't "natively" infect had to have been changed to enable them to grow in such cells, and that this change sufficiently attenuates the infectivity of the virus in humans to enable it to be used as a vaccine. $\endgroup$ – theorist Oct 5 '20 at 3:30
  • $\begingroup$ However, the passaging sequence you describe for measles (human kidney cells->human amnion cells->fertilized hen's eggs->chick embryonic cells) suggests that non-native infectivity is easier to achieve when you use immature cells than adult cells. I assume that's why they had to first get the virus to infect highly undifferentiated cells (fertilized egg) before it could infect slightly more mature cells (embryonic). This suggests the attenuated virus wouldn't be able to infect an adult chicken, so my question remains: Why is a virus that can't infect an adult able to infect immature cells? $\endgroup$ – theorist Oct 5 '20 at 3:31

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