With COVID-19, questions about how infections cause lasting immunity, or don’t, and how you know and what it all means for vaccines have become a matter of public focus.

But some immunologists have been pondering those questions for years.

“The immune system has a very good memory,” Bali Pulendran told BioWorld. “Clearly, some viruses and some pathogens can enter the body and stimulate the immune system, and the immune system can remember that encounter for decades.”

Yellow fever, whether as an infection or as a vaccine, is a prime example. Modeling studies suggest that immunity to yellow fever, after either an infection or a single shot of vaccine, lasts for several thousand years.

The other extreme is HIV, to which there is no natural immunity, and which has stymied all attempts at lasting vaccine-induced immunity to date.

Somewhere in the middle are diseases like the flu, where the usual recommendation is to wait with getting vaccinated until October, so that the resulting immune memory will last through the season.

And for COVID-19, of course, no one knows yet how long-lasting immunity will be.

Part of the challenge for developing a lasting vaccine is that some viruses like HIV and influenza virus mutate very rapidly.

But for other pathogens, immunity simply wanes.

Pulendran, who is professor of pathology and of microbiology and immunology at Stanford University, has spent his career looking for immune responses that are critical for lasting immunity, and building vaccines that attempt to elicit those responses.

One of his team’s early insights was that the most successful vaccines have been weakened live vaccines, and they have stimulated innate immune response by activating toll-like receptors (TLRs). By using TLR-stimulating adjuvants, Pulendran and his team have since improved the immune response to both influenza and, most recently, to HIV antigens. 3M-052, the TLR agonist used in the latter study, is currently being tested as an adjuvant for an HIV vaccine in a phase I trial.

The right kind of anger

Adjuvants are sometimes thought of as a way to rile up the immune system whose details don’t matter. But David Underhill told BioWorld, “the kind of angry that you evoke from the immune system is important.”

Underhill, who is professor and chair of the Department of Biomedical Sciences at Cedars-Sinai Medical Center, does research on Staphylococcus aureus, another pathogen where infection does not lead to lasting immunity.

His team has recently published a study showing that by delivering S. aureus antigens in a shell made of the yeast cell wall component β-glucan, they were able to evoke an effective immune response against the bacterium in mouse models of infection.

The rise of Candida auris notwithstanding, in general, “our immunity to fungi is really very good,” Underhill said. “Healthy people don’t stay home from work because they got a fungal infection.”

Immunocompromised individuals, however, can become susceptible to fungal infections. And when they do, they also become more susceptible to staph.

Looking at the literature, Underhill said, he realized that in reports of co-infections, “it was always fungal infections and staph infections… Not flu, not pneumonia.”

That link “suggests that the kind of immunity that the body mounts against fungi must be quite similar to the kind of immunity that the body wants against staph.”

Underhill and his colleagues tested their idea by constructing a Trojan Yeast of sorts – a shell of fungal β-glucan particles loaded with four S. aureus antigens, which they called 4X-SA-GP.

The vaccine was effective for up to eight weeks after vaccination.

Mice vaccinated once a week for three weeks with 4X-SA-GP developed both an antibody and a T-cell response to vaccination.

Underhill pointed out that although vaccine development tends to focus mainly on evoking a neutralizing antibody response, “in our mice, that T-cell-mediated immunity was really critical for the protection. If we’d optimized the vaccine for antibodies…. It wouldn’t have worked as well.”

Given that immunity to coronaviruses appears to wane, whether lasting immunity results from infection with SARS-CoV-2, and whether a vaccine can produce such lasting immunity, is a major concern.

Earlier in August, researchers reported the first solid of reinfection with the virus, in an immunocompetent resident of Hong Kong who became infected with two distinct strains of the virus 142 days apart.

Although the case report inevitably raised worries about whether permanent immunity to SARS-CoV-2 is possible, it is also important to note that this is the first case of reinfection that has been confirmed, out of 24 million confirmed infections.

Furthermore, the patient’s second infection was asymptomatic, suggesting that they might have developed functional immunity that prevented illness from his first infection, even if they did not develop the sterilizing immunity that would prevent reinfection altogether.

Finally, Pulendran pointed out that there is a difference between durable immunity in infected people versus durability in vaccinated people.

There is not necessarily “an equivalency between what infection does and what we aspire to do with a vaccine,” he said.

“Is it possible to develop a long-lasting COVID-19 vaccine?” he asked. “You betcha. I think that with the right adjuvant we could.”