Skin vaccination can generate protective CD8 T-cells to fight sexually transmitted infections (STIs)


In a study published today in the Nature Communications, researchers from King’s College London have shown how skin vaccination can generate protective CD8 T-cells that are recruited to the genital tissues and could be used as a vaccination strategy for sexually transmitted infections (STIs).

One of the challenges in developing vaccines for STIs, such as HIV or herpes simplex virus, is understanding how to attract specialised immune cells, called CD8 T-cells, to take up residence in the part of the body where the virus first enters.

These cells need to be in place, armed and ready to provide an immediate protective immune defence, rather than waiting for immune cells in the blood to enter the tissues which takes time.

Before this study, it was thought that vaccines ideally needed to be delivered directly to the body surface (e.g. female genital tissue) where the infection might start, so that the immune system can generate these CD8 T-cells, travel back to the vaccination site and eliminate any future virus that is encountered.

However, delivering vaccines directly to the female genital tissue is neither patient friendly nor efficient.

Now the team from King’s have found that their vaccination strategy marshals a platoon of immune cells, called innate lymphoid cells (ILC1) and monocytes, in the genital tissues to work together and release chemicals (chemokines) to send out a call to the CD8 T-cells generated by the vaccine to troop into the genital tissue.

Almost all licensed vaccines are thought to mediate protection through antibody production; therefore, antigen discovery research and development has focused largely on the identification of antigens that induce protective antibodies.1 

The availability of serum, the ease of working with antibodies, and, more recently, advances in microarray technology have facilitated these efforts.

However, vaccine development for some of the most devastating infectious diseases, such as malaria, tuberculosis (TB), and HIV, has met with limited success, partially because these organisms have intracellular life cycle stages that are not targeted by antibodies, and they have developed sophisticated mechanisms to avoid clearance by host immune responses.2 

Since T cells have been implicated in protection from these diseases,34567 considerable efforts have been directed at developing vaccines that induce protective T cell responses.

However, for infectious agents with large genomes that express many potential T cell antigens such as parasites and bacteria, many of the specific antigens that are targeted by protective CD8+ T cells are not known.

Identification of the target antigens of protective T cell responses would greatly facilitate vaccine development.

Malaria killed approximately 429,000 people in 2015,8 most of them children, in sub-Saharan Africa.

Despite decades of effort, a highly effective malaria vaccine is not available.

Immunization with attenuated Plasmodium sporozoites can provide high levels of protection in mice, non-human primates, and humans.9101112 

Protection is mediated by CD8+ T cells, which target a set of mostly unknown pre-erythrocytic stage antigens.131415161718

Activated CD8+ T cells can kill infected hepatocytes, thereby preventing blood-stage infection, which is responsible for the clinical symptoms of the disease.

However, substantial delivery issues are a considerable barrier to licensure of live sporozoite-based vaccines, and broad protection against circulating strains has not been demonstrated.

An alternative approach is to identify the targets of these protective CD8+ T cell responses and formulate them into a multivalent subunit vaccine designed to induce sustained T cell immunity.

The two P. falciparum sporozoite vaccines that are associated with high levels of protection in humans are radiation-attenuated sporozoites (RAS) and live sporozoites with concomitant chloroquine treatment to kill newly emerging blood-stage parasites (SPZ+CQ).

Immunization with RAS leads to infection of hepatocytes and expression of a set of early liver-stage genes, but these attenuated sporozoites do not develop into late liver and blood stages.19 

In BALB/c mice, the protective T cell response following vaccination with RAS is dominated by CD8+ T cells specific for the major surface protein on the sporozoite, the circumsporozoite protein (CSP), although T cell responses specific for other antigens can also contribute to protection.20

 In humans, T cell responses specific for several antigens have been observed following RAS immunization.212223 

In contrast to RAS, vaccination with SPZ+CQ allows expression of the full repertoire of liver-stage genes and replication of the parasite in hepatocytes.24 

Unlike RAS, where protection requires approximately 1,000 bites from infected mosquitoes, SPZ+CQ can provide durable protection in volunteers with as few as 30–45 bites.25 

This robust protection is strictly dependent on CD8+ T cells26 and immune response to CSP is not required, highlighting the fact that the specific antigen targets of protective immunity are not known.27

In this report, we describe a novel platform for the discovery of antigens that are the targets of T cell responses to infection (Figure 1).

Using this system, we identified 69 pre-erythrocytic antigens that were targeted by CD8+ T cell responses in mice immunized with protective regimens of P. yoelii SPZ+CQ.

Moreover, we demonstrated that the antigen that recalled the highest frequency of interferon gamma (IFNγ)-expressing CD8+ T cells, PY02605, provided sterile protection in mice when delivered in a DNA prime-adenovector boost regimen.

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Figure 1

Schematic View of High-Throughput Ad-Array Generation and Antigen Identification Assays
The general steps involved in generating a defined array of adenovectors and their use in antigen discovery screens using high-throughput technology are indicated.

This research builds on the team’s earlier work to develop skin vaccination techniques using a dissolvable ‘microneedle’ vaccine patch that once placed against the skin dissolves and releases the vaccine without requiring a hypodermic needle injection and generates immune responses.

Lead author, Professor Linda Klavinskis from King’s College London said: “This study highlights how specialised groups of ‘innate’ immune cells in distant tissues can be harnessed to attract protective CD8 T-cells, arming the body’s frontline tissues from infection.

“We now need to confirm these results with other types of vaccines from the one used in the study to see if a common pathway is triggered by skin vaccination.

If proven, this could have a significant impact in improving the effectiveness of vaccines against sexually transmitted infections.”

Journal information: Nature Communications
Provided by King’s College London


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