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How to develop transmissible vaccines?

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Subash Chapagain
Subash Chapagain Apr 21, 2022
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Viruses and other pathogens transmit all the time, causing diseases and pandemics. What if we could hijack their systems to turn viruses into vaccines that transmit?
Background:
Though vaccines are the best armours against infection and they have been proven to protect hosts, the full potential of vaccination is far from realized. In cases of rapidly transmitting infections, it is even more important to vaccinate the population at a rate that is faster than the actual disease transmission if we are to attain herd immunity. However, this seems to be very challenging when logistical, social and other reasons are factored in.
For (re)emerging pathogens that can spill to humans from wildlife, the application of preventive vaccines to curtail the potential emergence is still an idea confined in theory. To proactively tackle the issue of spillover and zoonoses from wildlife, and to reach herd immunity in the human population at a faster rate, a new approach to vaccination is being heavily pursued, at least in experimental field trials. A study very recently published in PLOS Biology describes a systematic approach to using a ‘transmissible’ (or self-disseminating) vaccine. In their study, the scientists used Desmodus rotundus betaherpesvirus (DrBHV) as a vector for a vaccine strain of bat-transmitted rabies; resulting in a vaccine strain that the bats pass among each other with natural benign infections. Earlier, another group had reported the development of a transmissible vaccine against myxomatosis and rabbit hemorrhagic disease (RHD) based on a recombinant myxoma virus that contained RHDV capsid protein. In this field trial, the recombinant transmissible virus was able to protect at least 50% of the rabbit population without any undesirable consequences .
How do these transmissible vaccines work? First, an ideal vector is identified. This ideal vector is any virus that circulates naturally among the target population without causing any disease (there are many such viruses). Next, the viral vector genome is edited using genetic engineering to incorporate a portion of the pathogen that is recognized by the immune system of the animal reservoir. This process endows the vector virus with the capacity to induce immunity to the pathogen in question. When the pathogen gene is optimally carried by the vector, the resulting vaccine will efficiently transmit among the animals and offer natural immunization as it transmits. In principle, this is elegant and straightforward.
Current issues and challenges:
  1. The intrinsic high mutational frequency of viruses makes it harder to maintain the homogeneity of the viral vector over time.
  2. The evolutionary loss of transgene function is another issue: with each replication in the animal host, the vaccine can gradually lose its capacity to induce effective immunity.
However, given our current understanding of viruses, immunology and epidemiology, this is an attainable feat. Once developed, the vaccine candidates can be tried in captive animals and then gradually upscaled to semi-natural to natural environments for controlling zoonoses. How do you think we can create the best vaccines that transmit on their own? Can you think of other alternative ways?

[1]https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001580

[2]https://www.sciencedirect.com/science/article/pii/S0264410X01001840?via%3Dihub

vaccines
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Creative contributions

Superinfection could be a useful feature when choosing a vector for transmissible vaccine

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Subash Chapagain
Subash Chapagain Apr 22, 2022
Superinfection is the biological process when a cell/organism previously infected by one virus gets co-infected with a different strain of the same virus later on. This feature can be extremely useful if we are to design vaccines that transmit, to address the issue raised by Michaela D in the contribution above. Generally, cells/organisms would develop immunity against a pathogen upon their first encounter and develop a lasting immunological memory that will fight off the pathogen later on with the antibodies produced using that memory. Though in normal conditions this is a highly desirable default biological process, for virus vaccines this might be a downside because if we have to introduce a new vaccine variant to counter the temporal inefficiency of vaccine resulting from mutations (which is expected). However, if we can find a viral vector that is capable of infecting AGAIN the cells that the original variant of the vector infected in the past, the new vaccine would work as effectively as the old one. In fact, this is exactly what the researchers found in this study. Using genomic sequencing to determine the overall patterns , they found that DrBHV can infect bats previously infected by other strains of DrBHV and that preexisting immunity may not hinder the transmissible vaccine if DrBHV vector is used. This finding is very exciting and sets a new roadmap to develop such self-disseminating vaccines.
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Vaccine viruses with a "deactivation trigger" that is pulled when they are not effective anymore

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Michaela D
Michaela D Apr 21, 2022
As you mentioned, the more a virus replicates the more mutations it accumulates. As a result, the transgene (the vaccine part) will also accumulate mutations and at some point, it may change too much to induce immunity anymore. A solution would be to reintroduce in the population the virus with the original transgene. However, the new virus-vaccine will have to compete with the older, mutated, one. I assume that for people that have been infected with old virus-vaccine (which is not effective anymore) will be harder to gain vaccine immunity from the new virus-vaccine? That is because their immune system will remember the virus and fight it before it gets the chance to integrate in the cells.
A solution to that would be to introduce in the virus-vaccine a "deactivation trigger" that is pulled when they reach a certain number of mutations. This number would be the number of mutations that would render the vaccine not relevant anymore.
How would we do that?
We would design the viral genetic material in a way that it can only tolerate a specific number of mutations. Once this number of mutations is reached the virus would not be able to replicate anymore. To get more technical: The ideal genetic part to focus is the part responsible for viral replication. For the genetic design: design the genetic sequence in such a way that is functinal for now but certain number of detrimental mutations will occur in a calculated time in the future.
As a result, the time the vaccine loses its effectiveness will coincide with the time the virus stops replicating. So, when we reintroduce the original, effective virus, it will not have to compete with the old one.
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jnikola
jnikola3 years ago
Very interesting suggestion. It could work. Do you know some techniques for how you can increase the rate of mutations in certain regions/gene parts? You should make sure the mutation rates of the replication and "effectiveness" genes are the same.
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Michaela D
Michaela D3 years ago
There are at least two techniques that can be used:
1) Some genetic sequences (single nucleotides to longer sequences) have been shown to be particularly prone to mutations . A good example is CG repeats (or CpG islands) where mutations occur 10 times higher than the average mutation rate .
2) Make it easier to result in a stop codon (that will stop the translation of mRNA and protein production). Based on the genetic code some codons only need one base change to result in a stop codon (silent mutation). For example, Tyrosine (codons: UAU and UAC) is very similar to two stop codons (UAA and UAG). So, by introducing Tyrosine (or Tryptophan or Cysteine) codons there are higher chances for stop codons to occur and for the protein not to be functional.
We can use the above information to design the vaccine sequence and the early viral sequence (as Subash Chapagain suggested). That would be in such a way that they become nonfunctional around the same time. Or that the viral sequence is the first to become nonfunctional, to allow for a margin of error and make sure that the virus does not keep replicating after the vaccine is not effective anymore.

[1]Iengar P. An analysis of substitution, deletion and insertion mutations in cancer genes. Nucleic Acids Res. 2012;40(14):6401-6413. doi:10.1093/nar/gks290

[2]Nachman MW, Crowell SL. Estimate of the mutation rate per nucleotide in humans. Genetics. 2000 Sep;156(1):297-304. doi: 10.1093/genetics/156.1.297. PMID: 10978293; PMCID: PMC1461236.

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Michaela D
Michaela D3 years ago
Is the idea clear?
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Herpes simplex virus as a self-transmissible vaccine?

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jnikola
jnikola Apr 27, 2022
I had a similar idea with herpes viruses in this session.
They are highly transmissible and stay usually forever in human nerve cells. If the symptoms were reduced and proteins of our choice introduced by genetic engineering, they could potentially be used as self-transmissible vaccines that reactivate when the immunity (or, preferably, the antibody concentration) drops below normal rates.
What do you think? Do these two sessions share something else?
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Subash Chapagain
Subash Chapagain3 years ago
Herpes simplex viruses are indeed excellent candidates when it comes to infectivity. However, for transmissibility, there can be some issues. For instance, HSVs are majorly contact-transmitted (most are sexually transmitted), and to engineer them for entirely different kinds of tropism for infection and cell entry in different tissue can be really challenging. Another issue related to HSV based gene vectors is the very short term transgene expression as a result of the functional deletion of all immediate-early (IE) genes. This can be an issue if the gene expression level (i.e. the level of encoded protein) is not enough to produce enough concentration of the protein to induce cellular immunity. However, this study shows a proof of concept that HSV can be engineered to achieve safe long-term transgene expression. Additionally, another issue I think is that HSVs are generally found to infect the cells of the nervous system, and if we want to use them as the carriers of vaccines, we need to engineer them for moderate infection of other cells and egress following it.
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jnikola
jnikola3 years ago
Subash Chapagain All true. I'll come back when I do some research. :)
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Create a chimeric peptide between a mosquito saliva protein and some viral capsid/envelope protein

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mschiav3
mschiav3 May 06, 2022
Very unusual idea, and very unfeasible considering biosafety, however, it will spread in nature very quicklly and you will have a reinforcement of the immune response every bite you get.
It may help to reach very isolated communities and it can be used in a gene drive system.
Not hard to develop but practically impossible to pass through regulation considering ethical and biosafety issues.
And it will not be transmissible by person 2 person but by mosquito 2 person.
Well, just a "fuel for thought" idea I guess.
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General comments

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Darko Savic
Darko Savic3 years ago
Omicron feels like a vaccine against other more dangerous Covid variants. It's more contagious and arguably less dangerous.
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Michaela D
Michaela D3 years ago
Darko Savic omicron is overall less dangerous but still lethal for some people.
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