Many countries are now becoming keenly aware that the creation of a vaccine to help control the spread of virulent respiratory infections like COVID-19 is only half the battle. Easy and effective vaccine delivery methods are a critically important step in the process. Yet, we need look no further than the 20th century for effective methods to help deliver pandemic vaccines. Among infectious diseases that have caused pandemics and epidemics, smallpox stands out as a success story. Smallpox vaccination led to the disease’s eradication in the 20th century. Until very recently, the smallpox vaccine was delivered using a technique known as skin scarification, in which the skin is repeatedly scratched with a needle before a solution of the vaccine is applied.
Nevertheless, today, almost all other vaccines are delivered via intramuscular injection, with a needle going directly into the muscle or through subcutaneous injection to the layer of tissue beneath the skin. But now, investigators at Harvard Medical School have reason to suspect that vaccines delivered by skin scarification may offer better protection against respiratory diseases.
As such, the authors present results from preclinical studies that suggest skin scarification may help generate lung T cells and provide protection against infectious diseases, with implications for prevention of COVID-19. The findings from this study were published recently in Npj vaccines through an article titled, “Epicutaneous immunization with modified vaccinia Ankara viral vectors generates superior T cell immunity against a respiratory viral challenge.”
“We have known for years that this technique was a good way to generate T cells that would home to the skin, but our study shows that skin scarification is also an effective way to generate T cells that home to the lungs,” explained senior study investigator Thomas Kupper, MD, chair of the department of dermatology at Harvard Medical School. “Vaccine development today is focused on selecting the best antigen(s) for T cells and B cells. But for a vaccine to work to its full potential, it also needs to direct T cells to where they are needed most. For respiratory pathogens, that means getting T cells to the lungs.”
Historically, smallpox vaccines used live vaccinia virus (VACV). More recently, the FDA has approved the use of modified vaccinia Ankara (MVA), a modern alternative that lacks about 10% of the parent genome and cannot replicate in human cells, thus avoiding the serious side effects seen with VACV. MVA, as a smallpox vaccine, is injected subcutaneously.
Kupper and colleagues set out to determine if the skin scarification route of immunization with MVA could provoke a more effective T cell response than other routes of immunization. The team inoculated mice using either skin scarification, intramuscular, subcutaneous, or intradermal injection. Skin scarification generated more T cells, produced greater numbers of lung-specific T cells, and provided superior protection against lethal viral doses than the others.
“Variola is transmitted by respiratory droplets, and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus than any other route of delivery, and at lower doses,” the authors wrote. “Comparisons of s.s. with intradermal, subcutaneous, or intramuscular routes showed that MVAOVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVAOVA s.s. produced greater numbers of lung Ova-specific CD8+ TRM and was superior in protecting mice against lethal VACVOVA respiratory challenge. Nearly as many lung TRM were generated with MVAOVA s.s. immunization compared to intra-tracheal immunization with MVAOVA and both routes vaccination protected mice against lethal pulmonary challenge with VACVOVA. Strikingly, MVAOVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization.”
“We used to think that lung-homing T cells could only be generated by direct lung infection, but here we find overlap between T cells appearing after lung infection and T cells generated through skin scarification,” Kupper added.
The authors note that their work is preclinical—until clinical trials are conducted in humans, it’s unknown if the phenomenon seen in the mouse model can be replicated in people. But the work has spurred the Kupper lab to explore the potential for using the MVA vector and skin scarification technique to develop more powerful—and potentially universal—vaccines against other infectious illnesses such as influenza and coronaviruses.
“We have known for a while that you can program T cells to go where you want them to go in the body—if you want protective T cells in the lungs, this is one way to achieve that. It is a serendipitous finding, but it seems to work very well,” Kupper concluded.
