Just over two years after our first blog on Covid-19, it appears that the disease is here to stay. Circulation rates are high enough that the hopes for eradication are low and, in a survey conducted by Nature, 90% of immunologists believe that the virus will become endemic and new strains will continue to emerge circulate (at least in pockets of the population) for years to come.
Of course, lots of diseases are endemic – including cold viruses, influenza, and malaria – and this is not necessarily a matter for concern. The size of the circulating population, infectiousness and severity of the disease, and the efficacy of treatment are all of course relevant factors. However, at time of writing, well over a million new cases per day are reported globally, there is no evidence that new variants are less infectious or deadly, and we are already seeing variants against which vaccines are less effective.
For those of us hoping to one day live without fear of Covid, the future at least appears to involve an annual booster shot. Consequently, there remains a general need for improved vaccines.
During infection, pathogenic antigens (fragments of pathogen-derived proteins) are displayed on antigen presenting dendritic cells. This promotes two parallel responses.
Firstly, antigens presented on MHC class I molecules activate CD8+ cytotoxic T cells, which hunt down and destroy other cells presenting the same peptide in this manner. All nucleated cells possess MHC class I on their surface and display peptides derived from degradation of various proteins within their cytosol. As such, all cells infected by a pathogen will display antigen peptides, and can be eliminated by cytotoxic T cells before the infection can spread further. A portion of “memory” CD8+ cells linger after the infection, providing an enhanced protective response if the same antigen is re-encountered. This is also known as the “endogenous pathway”.
Meanwhile, peptides degraded through the endocytic pathway are presented on MHC class II molecules, which are only present on “professional” antigen presenting cells. These activate so-called “helper” CD4+ T cells which, in turn, drive the development of antibody-producing B cells. These include plasma cells, which secrete antibodies, and memory B cells, which mediate longer term immune memory against future challenge. This second pathway advantageously generates antibody-mediated memory which is capable of binding and destroying pathogens even before they infect cells.
Vaccines allow recipients to acquire immunity through antigen challenge without exposure to disease-causing agents, typically through administration of attenuated pathogen of pathogen-derived peptides to the patient directly. Whilst all vaccines will operate through the antibody-generating and cytotoxic T cell methods, the antigens used in most modern vaccines are selected to maximise action through the second pathway. The DNA- and mRNA-based vaccines rolled out so far during the pandemic improve upon this method by administering a nucleic acid encoding the antigen into the patient, which is then produced by the patient’s cells in situ, generating antibodies as normal. This avoids issues with producing antigenic proteins ex vivo to the purity demanded by medical use, allowing vaccines to reach the clinic faster.
However, a new class of vaccines are designed to induce a cytotoxic T cell response of sufficient magnitude to provide a population of memory T cells. Unlike neutralising antibodies, T cells do not prevent infection, because they act only after a virus has entered the body. However, they are a key mechanism for clearing infections which are already underway, and memory T cells can provide protection in a manner that mimics natural immunity.
T cell eliciting vaccines and next-gen immunity
Many next generation vaccines against Covid-19 are moving away from antibodies and towards eliciting a T cell response.
This approach has several advantages. Firstly, as only surface proteins (such as the COVID-19 spike protein) are viable targets for antibodies, there are relatively few antigens available for use in antibody-generating vaccines. Furthermore, as in the case of the COVID-19 spike protein, these surface proteins can be highly variable may escape immunity through mutation. In contrast, T cell response can target viral internal proteins or those which are only present inside infected cells. In addition to providing additional targets, many of these proteins are key for viral reproduction and mutate far less frequently, and thus providing more stable targets.
Another potential benefit is that T cell inducing vaccines are likely to provide protection for longer. CD4-mediated memory is shorter-lived than that mediated through CD8, as can be seen with antibody-mediated influenza vaccines, which quickly lose efficacy. Indeed, at the time of writing, many recipients of antibody-inducing COVID-19 vaccines will be booking in for additional booster jabs in order to offset their rapidly declining protection.
Several T cell inducing vaccines are currently in development. Scancell’s COVIDITY vaccine is a DNA vaccine which encodes antigens not only for the spike (S) protein expressed on the viral surface as well as the internal nucleocapsid (N) protein. As the N protein is highly conserved amongst coronaviruses, this vaccine has the potential to provide protection effective against future strains of coronavirus. The COVIDITY vaccine also presents the antigen in a novel manner. The DNA sequence encodes a protein in the form of an antibody where the antigen binding domains are substituted with the epitopes. When the DNA form is taken up and expressed by the patient’s cells, the protein form is capable of binding to the high-affinity antigen Fc receptor on dendritic cells. This results in “cross-presentation”, and the generation of a robust T cell response alongside neutralising antibodies.
The Vaxart VAAST vaccine also targets the S and N protein, and induces a robust T cell response. These are delivered as DNA using an adenoviral vector, which also encodes an adjuvant alongside the antigen sequence. As similar methods were used to deliver the AstraZeneca and Johnson & Johnson vaccines earlier in the pandemic, the public may be more accepting of this vaccine.
Multiple challenges remain for the rollout of T cell eliciting vaccines. In the main, selecting suitable antigens for eliciting T cell responses remains difficult to predict, and requires analysis of infected cells. Furthermore, whilst proponents of T cell vaccines suggest that they can produce a more “natural” immunity profile by administering multiple antigens simultaneously, it remains to be seen if this can be achieved without significantly increasing the complexity of design and manufacture. Finally, and as ever, production of vaccines at the scale required for their mass rollout remains a significant challenge, especially as vaccination rates remain low in much of the developing world.
You won’t feel a scratch – vaccine delivery beyond the needle
The prospect of further or even annual Covid-19 boosters is not a welcoming prospect to those who, like the author, suffer from trypanophobia (the fear of needles). However, the good news is that as well as new mechanisms of action, the next generation of Covid-19 vaccines may well dispense with the injection altogether.
The Vaxart VAAST vaccines are administered in the form of a pill targeting the small bowel. This allows vaccines to engage the very active immune system and, unlike intramuscular injections, elicit mucosal immune responses more similar to those experienced in natural infection. Meanwhile, the Scacell COVIDITY vaccine has been developed for administration via PharmaJet’s needle-free injection technology, which offers significant safety improvements over historic spring-powered jet injectors. Another T cell inducing vaccine under development by Emergex is administered through a microneedle patch. This vaccine has recently received approval for a Phase I clinical trial.
As well as facilitating delivery to the patient, these alternative routes of delivery may also simplify delivery to the clinic, as room temperature stable tablets can be distributed more easily without cold chain logistics. Indeed, unlike hypodermic injection, they could be administered even without a trained healthcare professional, allowing effective rollout during mass vaccination.
The speed at which a coronavirus vaccine was developed is genuinely staggering and the WHO estimate that Covid-19 vaccinations reduced the number of deaths to the disease by approximately half. This achievement cannot be understated and, indeed, has not been. The inventors of mRNA vaccine technology were recognised as co-recipients of the 2022 Breakthrough Prize and it would be reasonable to wonder if a Nobel may not be far behind. However, as society begins to transition away from responding to the specific crisis of Covid-19 and towards managing coronavirus infections in the long term, the next generation of vaccines can hopefully bring some much needed security for years to come.
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