Why Are Oral Vaccines Not Extra Widespread?

In the 1970s, as waves of severe diarrhea swept across hospital nurseries in Melbourne, Royal Children’s Hospital virologist Ruth Bishop and her team set out to investigate the cause. Electron microscopy of the affected infants’ stool samples revealed a wheel-like virus, which they called the rotavirus.¹

Bishop and her team followed up on the children until they turned three and observed that rotavirus reinfected several kids. However, most of the children who suffered from infections of an unusual rotavirus strain—later dubbed RV3—as newborns showed significantly milder symptoms during the second bout of infection.^2,3

There’s something very simple about oral vaccination. It doesn’t involve needles. It doesn’t hurt a baby. In fact, some babies like the vaccine. It’s quite sweet.

—Julie Bines, Murdoch Children’s Research Institute

“[This] gave evidence that…an episode of infection can protect against subsequent infection and disease due to rotavirus,” said Julie Bines, an enteric disease researcher at Murdoch Children’s Research Institute. “And therefore, it is possible then [that] a vaccine delivered orally like the natural infection could result in some sort of immune process in the gut.”

Based on this evidence, decades after Bishop’s groundbreaking discovery, Bines and her colleagues developed and tested an oral rotavirus vaccine called RV3-BB.^4,5 To Bines, the vaccine delivery route was obvious. Since rotaviruses are transmitted by the fecal-oral route, “the ideal place to be protected is actually on the gut lining and the gut immune system,” said Bines. However, this was only one of the reasons.

“There’s something very simple about oral vaccination,” noted Bines. “It doesn’t involve needles. It doesn’t hurt a baby. In fact, some babies like the vaccine. It’s quite sweet.”

Emma Slack, a mucosal immunologist who develops oral vaccines at ETH Zürich, agreed that oral vaccinations are simple. “You don’t actually need trained medical staff to administer oral vaccines…so that makes them useful in crisis settings,” she said. This could significantly improve immunization rates in some parts of the world.

Historically, oral vaccines have been instrumental in fighting against infectious diseases. The oral polio vaccine played an important role in the fight to eradicating polio: It helped reduce the global polio cases by more than 99 percent since 1988.

Despite significant advancements since then and the advantages of oral vaccines, scientists have not been able to harness the full potential of oral vaccines due to several obstacles.⁶ One of the main challenges is that oral vaccines must remain potent despite the highly acidic pH of the stomach, changing pH throughout the digestive tract, and gastrointestinal enzymes that can break down proteins. The composition of the gut microbiome can also significantly affect the efficacy of oral vaccines. To overcome these challenges and promote more oral vaccines, scientists turn to various methods, such as altering formulations and using alternate approaches such as nanoparticle-based delivery.⁷

Oral Vaccines Offer Several Advantages

[A] certain amount of vaccine hesitancy is due to fear of needles. It’s kind of hard to quantitate that, but it’s clearly out there.

—Marcus Horwitz, University of California, Los Angeles

Oral delivery exposes the vaccine antigen to the gut-based mucosal immune system, which contains up to 80 percent of the body’s immune cells.⁸ Gut-dwelling antigen-presenting cells take up this antigen and present it to other immune cells, triggering a cascade involving both T cell-mediated cellular immunity and antibody-mediated humoral immunity.⁶

Antibodies evoke a response at both the gut lining—the mucosal surface—and systemically throughout the whole body. Unlike oral vaccines, injected vaccines elicit only a systemic immune response via the blood.

Slack noted that several pathogens infect humans via one of the mucosal surfaces such as the intestines, lungs, or urogenital tracts. “If we inject vaccines, you get a good immune response in the blood and in the tissues, but you get a much less good response at those surfaces,” she noted.

Aside from potentially offering more comprehensive immunity, needle-free vaccinations also provide a few other advantages. “[A] certain amount of vaccine hesitancy is due to fear of needles. It’s kind of hard to quantitate that, but it’s clearly out there,” said Marcus Horwitz, an immunologist at the University of California, Los Angeles. “So, some people who otherwise might not be willing to be vaccinated [via injections], would be willing to be vaccinated with an oral vaccine.” He added that oral vaccines are also relatively cheaper to produce, which translates to a more affordable vaccine.

These advantages, combined with the fact that people can self-administer oral vaccines prompted Horwitz and his team to develop an oral vaccine against COVID-19 in 2023. The researchers iterated an oral version of an injectable vaccine they had previously developed and tested it in hamsters.⁹ The oral vaccine protected the animals from severe symptoms of COVID-19, including preventing severe weight loss and changes in lung pathology. However, the journey to achieving these results was not straightforward.

Barriers to Oral Vaccines

“One of the challenges that we had to deal with was getting the vaccine through the stomach,” said Horwitz. The stomach is highly acidic which aids in digestion and protection against pathogens. However, this can destabilize oral vaccines or their constituents, leading to reduced potency.

While the pH of infant stomachs is more neutral than that of older children and adults, orally administering vaccines to young kids poses separate obstacles that might impact their immune responses.¹⁰ “One of the major challenges to oral vaccines are potentially breastmilk,” said Bines.

Breastmilk contains antibodies as well as other factors which inhibit rotavirus replication, which could impair rotavirus vaccine performance.¹¹ In several studies, scientists reported a correlation between breastmilk composition and the level of immune response triggered by oral rotavirus vaccines.

Breastmilk from mothers in developing countries contains more anti-rotavirus antibodies compared to that from mothers in developed countries.¹² Parallelly, oral rotavirus vaccines are highly effective in developed countries, but not as much in developing countries.¹³ Several scientists propose that differences in breastmilk composition could contribute to the variability of vaccine success, suggesting that breastmilk antibodies may impede vaccine potency.

The complexity of the intestinal environment, which consists of cells, fluids, and broken-down food, further complicates matters. “Out of that sort of very complicated soup, your vaccine needs to be selected into the immune system and actually seen,” said Slack.

One of the ingredients of this “soup” within the digestive tract is a thriving community of trillions of microorganisms including bacteria, viruses, archaea, and fungi. The gut microbiota plays a crucial role in shaping host immune responses, which can impact responses to oral vaccines.

“There is a concern that that [the] type of microbiome may create a barrier either by binding or interfering in some ways of an oral vaccine,” said Bines. Indeed, studying the diversity of the gut microbiota in infants revealed that greater diversity was linked with a poorer oral rotavirus vaccine immune response.¹⁵

Despite these significant obstacles to oral vaccinations, Bines said, “There are ways to get around those barriers.”

Overcoming Challenges to Oral Vaccines: Learnings from the Lab

Since the vector that Horwitz and his team used for developing the oral vaccine against COVID-19 was sensitive to acidic pH, the researchers treated hamsters with a sodium bicarbonate solution to neutralize their stomach acid. This ensured that the vaccine would stay intact and activate an immune response.

However, according to him, there could be a simpler alternative in humans. “You can give someone a [vaccine in a] capsule which is resistant to acid, and it just passes through the stomach,” said Horwitz. “And when it gets into the small intestine at the higher pH, then the capsule is dissolved, and you release the contents.”

Other scientists have also explored using bacterial or yeast spores, which can persist in the gut and secrete the constituents there.¹⁶ Using Bacillus subtilis spores, scientists developed a vaccine against the COVID-19 virus SARS-CoV-2, which has shown some promise.¹⁷ Researchers have also tested encapsulating antigens within nanoparticles or liposomes—spherical vesicles made of lipid bilayers—to protect them from getting degraded by gastric acid. Although in vivo studies show positive results, few nanoparticle-based oral vaccines have made it to clinical trials.^18,7

Some other in vivo studies have offered alternatives. “There’s a lot of work being done on, for example, different sugar structures or different sugar binding proteins that actually help really deliver the vaccines to the right place in the gut,” said Slack. For instance, delivering oral vaccines against Shigella using glycosylated nanoparticles in rabbits triggered the appropriate immune response.¹⁹

Horwitz hopes that such approaches reduce the barrier to having successful oral vaccines. “The future probably is going to be these modern technologies that are being developed, nanoparticles, liposomes and so on,” he said.

Giving Oral Vaccines a Fighting Chance in Clinical Trials

While these approaches could help overcome the obstacles to oral vaccine success in older children or adults, Bines and other researchers who work on neonatal vaccinations face challenges in breastfeeding babies. To tackle any components of breastmilk from impairing vaccine potency, scientists conducted clinical trials wherein they stopped mothers from breastfeeding for an hour before and after giving infants the oral rotavirus vaccination.^20,21 However, this did not significantly improve vaccine efficacy, suggesting that factors other than maternal anti-rotavirus antibodies probably play a role in the variability of vaccine success.

Since one such factor is the baby’s gut microbiota diversity, Bines and her team sought to overcome this challenge. Usually, six-week-old babies receive the oral rotavirus vaccine, by which time their gut microbiomes are already relatively well-developed.

“If you give the vaccines early—and we’ve been giving the vaccine from birth—in the first week of life, then you can overcome that because the babies haven’t got all this complexity of [gut] microbiome that might in fact create a barrier,” said Bines. Consistent with this, she and her team found that vaccinating babies at birth led to a greater number of friendly bacteria, better protecting the newborns against infection during the first weeks of their lives.²²

Despite several oral vaccines being developed due to their obvious advantages, Slack noted that many of them fail in clinical trials. She believes one reason behind this is that at the preclinical stage, scientists test vaccines in mice that are housed in clean and controlled facilities. This means they carry limited microbes as part of their microbiomes.

In contrast, trillions of different microbes make up the human microbiome. “Understanding how [the microbiome] affects uptake and presentation of mucosal vaccines is going to be key to overcoming this translation barrier,” said Slack.

“We have good oral vaccines now,” agreed Bines. “We just have to think smart about how we deliver them,” she said. “Maybe we should be thinking about the gut physiology a bit more so we can make sure those vaccines have the best chance to offer protection,” said Bines.