While the COVID-19 pandemic spreads, hunt for a reliable vaccine is in full swing. This will take time, and there are significant barriers, both technological and financial.
A lot has been said on this blog already about the role of TLRs in dendritic cells (DC)- the principal antigen presenting cell. DCs can be myeloid, ie CD11c+ or plasmacytoid, which are CD11c-. Myeloid DCs produce many cytokines, while plasmacytoid DCs mainly produce Class I interferons.
The set of cytokines that are produced by the DC will determine which type of T cell response is activated- Th1 or Th2. In general, strong antigenic stimulation produces a Th1 response, while a weak stimulus to the DC produces a Th2 response. A Th1 response leads to activation of both cellular and humoral (antibody mediated) immunity, while a Th2 response will only lead to humoral immunity. Cellular immunity, driven by Th1 response is essential for controlling intracellular infections with viruses, bacteria and fungi. A Th2 response will reduce viraemia or bacteraemia, but will not fight intracellular pathogens.
Th1 responses are initiated by IL-12 produced by the myeloid DC, which then leads to the production of interferon-gamma by NK, NK-T and T-cells. On the other hand, Th2 responses are initiated by IL-4, IL-5, IL-10 and IL-13.
Now here's the important bit. Th1 and Th2 responses inhibit each other. Thus a Th2 response will curtail a Th1 response and thus prevent that development of cellular immunity. This can have dire consequences against organisms such M.tuberculosis, M.leprae and Leishmaniasis, Listeria.
Successful vaccines, for the most part, elicit a Th1 response. If they elicit a Th2 response instead, in some cases the underlying infection will worsen. This has been one of the principal barriers to developing a vaccine against RSV and SARS. Fortunately, the original SARS started in Nov 2002 and fizzled out by July next year. Any efforts to produce a vaccine against that virus also petered out at this point. I suspect though that similar (Th1 v Th2 response) issues may apply to COVID19.
Vaccines often produce short lived responses. One way of prolonging the action of vaccines is to administer it with an adjuvant. The original vaccine adjuvant was alum. Unfortunately, this wasn't particularly useful because it elicited a predominantly Th2 response. On the other hand, Complete Freund's Adjuvant (CFA), which is comprised of inactivated BCG and a mixture of inactivated TLR ligands, elicits a strong Th1 response in animals. Unfortunately, it cannot be used in human beings.
Other adjuvants such as monophosphoryl ester (MPL) are strongly immunogenic and elicit a predominantly Th1 response. For example, Glaxo has used a combination of MPL and alum (the latter used to adsorb the vaccine) for its HPV vaccine and subcomponent vaccine against Herpes simplex.
Sometimes, antigenic peptides can be too small to elicit an immune response by itself. This can be got around by attaching them to a larger protein, that is more antigenic. One such candidate was the keyhole limpet haemocyanin, a very large copper containing protein derived from the endolymph of an inedible mollusc. Unfortunately, it elicits a Th2 response.
There has been more success with the LEAPS technology for making small peptides immunogenic . LEAPS stands for Ligand Epitope Antigen Presentation System. This attaches a 13- amino acid peptide sequence called J-ICBL from beta-2 microglobulin (which is present in all HLA Class I molecules) to the small antigenic peptide, and thus elicits a predominantly Th1 response. This has been used to prepare vaccines against Mycobacteria, Herpes simplex and Plasmodium.
Particles of a certain size- around one micron- are preferentially taken up by APCs and macrophages. This has been used in vaccine production through microparticles called PLG, which carry either positive or negative charge. Positively charged PLG attaches to DNA, while negatively charged PLG attaches to proteins.
One of the newer techniques for viral vaccines is to introduce the viral sequence into the DNA of a harmless Adenovirus, which can then be injected into the blood and elicit an immune response. The two main candidate vaccines against Ebola both use Adenovirus as a vector. Thus, the Ebola virus glycoprotein is presented in a replication-incompetent chimpanzee adenovirus 3 (cAd3) or a replication-competent vesicular stomatitis virus. A successful Phase I trial of the first was published in NEJM in 2017.
At the end of the day, developing a successful vaccine takes time and money. In 2000, the average cost of developing a new vaccine was 800 million dollars. Current costs would be much higher. Pharmaceutical companies devote an enormous amount of time, diverting skilled professionals, to the production of a vaccine that might never work, or may not see approval due to perceived side effects.
The latter has been a particular driver of litigation against drug companies. For example, the cost of DPT rose from $0.11 to $11.00 from 1981 to 1986 due to costs of litigation. This deters future investment in vaccine production.
Reference.
Rosenthal KS, Zimmerman D. Vaccines: All Things Considered. Clin Vaccine Immunol. 2006 Aug; 13: 821–829.
A lot has been said on this blog already about the role of TLRs in dendritic cells (DC)- the principal antigen presenting cell. DCs can be myeloid, ie CD11c+ or plasmacytoid, which are CD11c-. Myeloid DCs produce many cytokines, while plasmacytoid DCs mainly produce Class I interferons.
The set of cytokines that are produced by the DC will determine which type of T cell response is activated- Th1 or Th2. In general, strong antigenic stimulation produces a Th1 response, while a weak stimulus to the DC produces a Th2 response. A Th1 response leads to activation of both cellular and humoral (antibody mediated) immunity, while a Th2 response will only lead to humoral immunity. Cellular immunity, driven by Th1 response is essential for controlling intracellular infections with viruses, bacteria and fungi. A Th2 response will reduce viraemia or bacteraemia, but will not fight intracellular pathogens.
Th1 responses are initiated by IL-12 produced by the myeloid DC, which then leads to the production of interferon-gamma by NK, NK-T and T-cells. On the other hand, Th2 responses are initiated by IL-4, IL-5, IL-10 and IL-13.
Now here's the important bit. Th1 and Th2 responses inhibit each other. Thus a Th2 response will curtail a Th1 response and thus prevent that development of cellular immunity. This can have dire consequences against organisms such M.tuberculosis, M.leprae and Leishmaniasis, Listeria.
Successful vaccines, for the most part, elicit a Th1 response. If they elicit a Th2 response instead, in some cases the underlying infection will worsen. This has been one of the principal barriers to developing a vaccine against RSV and SARS. Fortunately, the original SARS started in Nov 2002 and fizzled out by July next year. Any efforts to produce a vaccine against that virus also petered out at this point. I suspect though that similar (Th1 v Th2 response) issues may apply to COVID19.
Vaccines often produce short lived responses. One way of prolonging the action of vaccines is to administer it with an adjuvant. The original vaccine adjuvant was alum. Unfortunately, this wasn't particularly useful because it elicited a predominantly Th2 response. On the other hand, Complete Freund's Adjuvant (CFA), which is comprised of inactivated BCG and a mixture of inactivated TLR ligands, elicits a strong Th1 response in animals. Unfortunately, it cannot be used in human beings.
Other adjuvants such as monophosphoryl ester (MPL) are strongly immunogenic and elicit a predominantly Th1 response. For example, Glaxo has used a combination of MPL and alum (the latter used to adsorb the vaccine) for its HPV vaccine and subcomponent vaccine against Herpes simplex.
Sometimes, antigenic peptides can be too small to elicit an immune response by itself. This can be got around by attaching them to a larger protein, that is more antigenic. One such candidate was the keyhole limpet haemocyanin, a very large copper containing protein derived from the endolymph of an inedible mollusc. Unfortunately, it elicits a Th2 response.
There has been more success with the LEAPS technology for making small peptides immunogenic . LEAPS stands for Ligand Epitope Antigen Presentation System. This attaches a 13- amino acid peptide sequence called J-ICBL from beta-2 microglobulin (which is present in all HLA Class I molecules) to the small antigenic peptide, and thus elicits a predominantly Th1 response. This has been used to prepare vaccines against Mycobacteria, Herpes simplex and Plasmodium.
Particles of a certain size- around one micron- are preferentially taken up by APCs and macrophages. This has been used in vaccine production through microparticles called PLG, which carry either positive or negative charge. Positively charged PLG attaches to DNA, while negatively charged PLG attaches to proteins.
One of the newer techniques for viral vaccines is to introduce the viral sequence into the DNA of a harmless Adenovirus, which can then be injected into the blood and elicit an immune response. The two main candidate vaccines against Ebola both use Adenovirus as a vector. Thus, the Ebola virus glycoprotein is presented in a replication-incompetent chimpanzee adenovirus 3 (cAd3) or a replication-competent vesicular stomatitis virus. A successful Phase I trial of the first was published in NEJM in 2017.
At the end of the day, developing a successful vaccine takes time and money. In 2000, the average cost of developing a new vaccine was 800 million dollars. Current costs would be much higher. Pharmaceutical companies devote an enormous amount of time, diverting skilled professionals, to the production of a vaccine that might never work, or may not see approval due to perceived side effects.
The latter has been a particular driver of litigation against drug companies. For example, the cost of DPT rose from $0.11 to $11.00 from 1981 to 1986 due to costs of litigation. This deters future investment in vaccine production.
Reference.
Rosenthal KS, Zimmerman D. Vaccines: All Things Considered. Clin Vaccine Immunol. 2006 Aug; 13: 821–829.
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