Down the hatch

At the time of writing, slightly more than two-thirds of the UK’s population are fully vaccinated. Opinion differs on exactly what percentage of the population needs to be vaccinated to achieve herd immunity, but if the statistics around measles are any barometer – according to the World Health Organisation, measles requires 95% of a population to be vaccinated – we are falling considerably short of the vaccine target for herd immunity against Covid-19, and the UK is doing better than most.

Only 61.6% of the world population has received at least one dose of the vaccine; and that figure drops to only 10.6% of people in low-income countries. In Nigeria, less than 3% of the population have been fully vaccinated. Globally, vaccination uptake is a problem; we are simply not reaching the numbers that we need to bring about an end to the pandemic. Those of us in the West who have been listening to the media, may be forgiven for assuming that this is the result of conspiracy theories and trumped-up anti-vaccine rhetoric, spreading like a parallel virus across the internet. Though misinformation has certainly played its part in vaccine hesitancy, there is more to this than simply rhetoric. As the director of public health at Hertfordshire County Council, Jim McManus explains, “the single thing to realise about improving vaccine uptake is that there is no single thing that will improve vaccine uptake”.

At the start of 2021, McManus published an article on ‘Tackling the big four vaccine challenges’, which he identifies as: structural barriers to equitable access; hesitancy; data; and disinformation. We need “a combination of measures”, McManus explains, including, “confidence and trust that the vaccine is safe and effective, through good quality information and good quality communication; ability to access the vaccine; and then ensuring that the means of getting the vaccine are acceptable”.

A lot has been made of vaccine hesitancy in the press – with most of it being blamed on nonsensical conspiracies – but McManus believes this is a misleading label. In reality, as McManus explains, people’s responses to the vaccine fall into a spectrum of categories, ranging from those “we could call anti-vaxxers”, to those who “are not hesitant [but] just want information”, to those “who really have problems with needles”.

Little mention has been made of this third group – and yet, they comprise a substantial part of the population. According to McManus, around 10% of the population suffer from trypanophobia (a fear of needles), and that is before you take into account the people with learning disabilities and people with autism. “And I would put them as a separate category of people from fear of needles, because it’s not needles that are the issue, it’s the significant disruption to a routine that they’re used to, and the needle is a part of that,” he explains.

Face the fear

The findings of one systematic review published in 2019 indicate that the majority of children exhibit trypanophobia, while prevalence estimates ranged 20–50% in adolescents, and 20–30% in young adults. This may be, as McManus suggests, something of an overstatement, but “there is no doubt that if an oral vaccine became available […] then that would make it easier for a portion of the public to take it up” – but that’s a big scientific “if”.

Oral vaccines are not unheard of. The rotavirus vaccine is administered orally to babies in the UK as a routine part of their childhood vaccinations and, for many years, polio vaccines were also given orally – though, as Professor Azeem Majeed, head of department of primary care and public health at Imperial College London, notes, “this has now been replaced [in the UK] by an injected vaccine”.

Like McManus, Majeed is sceptical about the chances of seeing an oral Covid-19 vaccine anytime soon. “I think it’s unlikely we will see oral vaccines for Covid-19 introduced in the near future,” he admits, because we simply “don’t know yet how well oral vaccines will work”. An oral vaccine for Covid-19 is not straightforward to produce, as a method is needed to stop it being broken down by the acid in the stomach.

Majeed’s point is not that an oral vaccine is an impossibility per se, rather, that our efforts may be better spent elsewhere. “The priority,” Majeed notes, “is vaccines that are much better at preventing infection than our current vaccines, reduce transmission of infection, and provide longer-term immunity. Current vaccines have limited effects in these areas, which is why we are still seeing high infection rates in the UK despite a high vaccine uptake in the population.” 

The race to freedom

Clearly, the UK has got its priorities right: the Oxford/ AstraZeneca vaccine was one of the world’s first internationally distributable vaccines. But there are biotech companies that were working on oral vaccines before the pandemic, and that have spent the past 18 months putting other programmes on hold to channel their efforts into the development of a viable oral vaccine for Covid-19.

Vaxart is one such company, with an oral Covid vaccine already in phase-II clinical trials – and so far, things are looking positive. “In a phase-I trial,” Dr Sean Tucker, chief scientific officer of Vaxart, explains, “the oral Covid-19 vaccine (VXA-CoV2-1) was well tolerated and induced substantial T cell responses, as well as an antibody response in the nose”. In fact, there may even be early signs that the oral vaccine has some medical advantages over the jab.

Findings from Vaxart’s preclinical studies, including a study published by Duke University last autumn, suggest that its Covid-19 vaccine may inhibit the airborne transfer of the virus better than an injected protein vaccine. “Because the nose is the first line of defence for respiratory pathogens,” Tucker explains, “we think there is a benefit in preventing infection by using our oral vaccine. Plus, the antibodies in the nose (IgA) tend to be more cross-reactive than the antibodies made by injected vaccines (IgG), so we believe we will show an improved ability to block the new variants of concern. Injected vaccines don’t really induce immune responses in the nose.”

It may be too soon to compare the efficacy of the two vaccine methods, but there is little doubt that a pill would have a number of clear strategic advantages, including the speed of administration, the lack of cold chain requirements, and the removal of a qualified healthcare professional to administer a jab. “In terms of manufacturing,” Tucker says, “the end step (tableting) is a lot easier than the sterile fill and finish of vials or needles. All of these advantages should translate to lower costs to get vaccines to people.” What is more, “a pill vaccine that is room temperature stable has global implications, particularly in the Southern Hemisphere and other parts of the world, where they don’t have the cold chain or healthcare infrastructures they need to support injections.”

Keep record

The advantages are obvious – so what might be the disadvantages? And, more importantly, what exactly are the chemical and biological barriers to vaccinating with an oral drug? Echoing Majeed, Tucker comments on the difficulties caused by “the low pH of the stomach. That destroys a lot of proteins and large biologicals like viruses. Some of the biological barriers [also] include immune recognition in the intestine. The intestine’s primary function is to intake food and turn it into energy, not to mount an immune response.” But he is confident that Vaxart has found ways around these problems.

“We solved the low pH problem by putting an enteric coating on our vaccine tablets [which] stays intact at low pH solution [thus protecting the contents from acid] and then falls apart at neutral pH, allowing the vaccine to come in contact with intestinal cells,” he says. “We solved the immune recognition problem by co-expressing a double-stranded RNA adjuvant with our protein target. This dsRNA tells the immune system to pay attention, create an immune response and develop memory so you’ll be protected if you ever ‘see’ the protein again.”

Then, there are potential issues around the traceability of an oral vaccine. “There is a concern,” as Majeed notes, “that people might be given an oral vaccine to take later but not actually use it (as sometimes happens with medication for other medical conditions).” Even if people did take it, “how do you prove you took the vaccine without a band-aid on your arm and a professional certifying that they gave you a jab?” Tucker asks. “There are technologies out there that could be used, but it’s not as simple.”

McManus, however, is confident that proof of vaccination should not pose a problem. “Every child in the UK has a vaccine record, and [one of] the vaccines that they get is oral [rotavirus],” he points out, “so why should it be any different [with a Covid-19 vaccine]? It’s a healthcare intervention so you’d keep a record of it.” If we can get oral vaccines made and approved, then healthcare systems in the most developed countries like the UK and the US should be sufficiently capable of keeping track of them through barcodes, safe chain custody, biological standards and detailed patient records.

Unfortunately, it does not look like we will get an oral vaccine anytime soon. Tucker optimistically estimates that Vaxart “could be in a position to request emergency use authorisation in about a year”, but even he has to admit that “this depends on what’s happening with new variants and outbreaks”.

Yet, if our lives are going to be marked out by biannual Covid-19 vaccine boosters, then the development of a pill seems like an important step, not only for those with trypanophobia, not only for neurodiverse groups, and not only for children, but for all of us. An oral solution may not be the magic pill that solves the vaccine question, but it will certainly sugarcoat it.