Editing DNA vaccine (section)

=== Cytotoxic T-cell responses ===

One of the advantages of DNA vaccines is that they are able to induce [[Cytotoxic T cell|cytotoxic T lymphocytes]] (CTL) without the inherent risk associated with live vaccines. CTL responses can be raised against [[Immunodominance#CTL Immunodominance|immunodominant]] and immunorecessive CTL epitopes,<ref name=Fu1997>{{cite journal | vauthors = Fu TM, Friedman A, Ulmer JB, Liu MA, Donnelly JJ | title = Protective cellular immunity: cytotoxic T-lymphocyte responses against dominant and recessive epitopes of influenza virus nucleoprotein induced by DNA immunization | journal = Journal of Virology | volume = 71 | issue = 4 | pages = 2715–2721 | date = April 1997 | pmid = 9060624 | pmc = 191393 | doi = 10.1128/JVI.71.4.2715-2721.1997 }}</ref> as well as [[Immunodominance#CTL Immunodominance|subdominant CTL epitopes]],<ref name=Chen1998 />{{technical inline|date = October 2021}} in a manner that appears to mimic natural [[infection]]. This may prove to be a useful tool in assessing CTL epitopes and their role in providing immunity.

Cytotoxic T-cells recognise small [[peptides]] (8-10 [[amino acids]]) complexed to [[MHC class I]] molecules.<ref name=Restifo1995 /> These peptides are derived from cytosolic proteins that are degraded and delivered to the nascent MHC class I molecule within the [[endoplasmic reticulum]] (ER).<ref name=Restifo1995>{{cite journal | vauthors = Restifo NP, Bacík I, Irvine KR, Yewdell JW, McCabe BJ, Anderson RW, Eisenlohr LC, Rosenberg SA, Bennink JR | display-authors = 6 | title = Antigen processing in vivo and the elicitation of primary CTL responses | journal = Journal of Immunology | volume = 154 | issue = 9 | pages = 4414–4422 | date = May 1995 | doi = 10.4049/jimmunol.154.9.4414 | pmid = 7722298 | pmc = 1952186 | url = http://www.jimmunol.org/cgi/content/abstract/154/9/4414 }}</ref> Targeting gene products directly to the ER (by the addition of an ER insertion signal sequence at the [[N-terminus]]) should thus enhance CTL responses. This was successfully demonstrated using recombinant [[vaccinia]] viruses expressing [[influenza]] proteins,<ref name=Restifo1995 /> but the principle should also be applicable to DNA vaccines. Targeting antigens for intracellular degradation (and thus entry into the MHC class I pathway) by the addition of [[ubiquitin]] [[Signal peptide|signal sequences]], or mutation of other signal sequences, was shown to be effective at increasing CTL responses.<ref name=Tobery1997 />

CTL responses can be enhanced by co-inoculation with co-stimulatory molecules such as [[CD80|B7-1]] or [[CD86|B7-2]] for DNA vaccines against influenza nucleoprotein,<ref name=Fu1997/><ref name=Iwasaki1997>{{cite journal | vauthors = Iwasaki A, Stiernholm BJ, Chan AK, Berinstein NL, Barber BH | title = Enhanced CTL responses mediated by plasmid DNA immunogens encoding costimulatory molecules and cytokines | journal = Journal of Immunology | volume = 158 | issue = 10 | pages = 4591–4601 | date = May 1997 | doi = 10.4049/jimmunol.158.10.4591 | pmid = 9144471 | s2cid = 41779568 | url = http://www.jimmunol.org/cgi/content/abstract/158/10/4591 }}</ref> or [[GM-CSF]] for DNA vaccines against the murine malaria model ''[[Plasmodium yoelii|P. yoelii]]''.<ref name=Weiss1998>{{cite journal | vauthors = Weiss WR, Ishii KJ, Hedstrom RC, Sedegah M, Ichino M, Barnhart K, Klinman DM, Hoffman SL | display-authors = 6 | title = A plasmid encoding murine granulocyte-macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine | journal = Journal of Immunology | volume = 161 | issue = 5 | pages = 2325–2332 | date = September 1998 | doi = 10.4049/jimmunol.161.5.2325 | pmid = 9725227 | s2cid = 21038927 | url = http://www.jimmunol.org/cgi/content/abstract/161/5/2325 | doi-access = free }}</ref> Co-inoculation with plasmids encoding co-stimulatory molecules IL-12 and TCA3 were shown to increase CTL activity against HIV-1 and influenza nucleoprotein antigens.<ref name=Iwasaki1997 /><ref name=Tsuji1997>{{cite journal | vauthors = Tsuji T, Hamajima K, Fukushima J, Xin KQ, Ishii N, Aoki I, Ishigatsubo Y, Tani K, Kawamoto S, Nitta Y, Miyazaki J, Koff WC, Okubo T, Okuda K | display-authors = 6 | title = Enhancement of cell-mediated immunity against HIV-1 induced by coinnoculation of plasmid-encoded HIV-1 antigen with plasmid expressing IL-12 | journal = Journal of Immunology | volume = 158 | issue = 8 | pages = 4008–4013 | date = April 1997 | doi = 10.4049/jimmunol.158.8.4008 | pmid = 9103472 | s2cid = 38099483 | url = http://www.jimmunol.org/cgi/content/abstract/158/8/4008 | doi-access = free }}</ref>