When we think of a vaccine, the first thing that comes to mind is an intimidatingly long needle attached to a syringe followed by a sharp poke in the arm.

But, with the Covid-19 pandemic, incredible innovation has been required to bring vaccines to the masses in a record amount of time. Some companies are innovating not only in regards to the vaccine formulation but also how it is delivered to the immune system, building on a long history of research and deployment of oral vaccines, nasal sprays and more.

A Covid-19 vaccine that doesn’t come in injectable form has a number of potential benefits. One is that it could avoid the need for refrigeration making it easier to ship and store. Another is that they need not be administered by a medical professional and can be sent directly to people’s homes or hard-to-reach areas where individuals can be given the vaccine to take themselves. And of course, another obvious benefit is for the one in ten people who have a phobia of needles.

Clinical Trials Arena tracks some of the vaccine developers exploring alternative ways to get vaccines into people’s bodies and how they could help overcome some of the bottlenecks and barriers that are stunting global rollout.


Oral vaccines: Vaxart’s VXA-CoV2-1

A poll conducted by Quadrant Strategies and commissioned by Vaxart, a San Francisco-based biotech dedicated to unlocking the full potential of oral vaccines, found that out of the 1,500 adult Americans surveyed, seven in 10 would prefer to take a pill rather than getting injected with a vaccine.

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“It is not surprising that seven in 10 Americans prefer a pill to getting stuck with a needle,” Vaxart chief science officer Sean Tucker said. “Needle injections present a barrier to getting people vaccinated and we have a solution that we believe will be effective and would allow people to avoid injections they don’t want to have.”

Nearly a quarter of respondents said they are afraid of needles and the poll observed that fear is found among all socioeconomic groups.

“We need to tear down this barrier to vaccinating more Americans,” said Vaxart CEO Andrei Floriou. “A pill option taken at home on their own time raises the number of Americans likely to get a Covid-19 vaccine in a material way.”.

Vaxart oral recombinant vaccines are formulated as tablets that are enterically coated for efficient delivery to the small bowel to protect the active ingredient from the acidic conditions in the stomach.

“By targeting the small bowel, the vaccines engage the finely-tuned immune system of the gut to generate broad systemic and mucosal immune responses for robust, persistent immunity,” said Vaxart.

Vaxart’s Covid-19 candidate, VXA-CoV2-1, employs the firm’s VAAST (Vector-Adjuvant-Antigen Standardized Technology) delivery platform which uses an engineered adenovirus type 5 (Ad5) vector that delivers two payloads to the cells of the mucosal epithelium of the small bowel. One payload is the gene coding for the selected pathogen-specific protein antigen. The other, is the gene coding for the Toll-Like Receptor-3 (TLR-3) agonist, an adjuvant that activates the innate immune system.

Vaxart’s vaccine also contains instructions for making the spike (S) protein and the nucleocapsid (N) protein. The N protein is crucial for the replication and assembly of the coronavirus. It provides another target for antibodies that can shut it down.

In May 2021, Vaxart reported the latest data from the Phase I trial of VXA-CoV2-1, which demonstrated broad cross-reactivity against other coronaviruses.

According to the trial data, VXA-CoV2-1 induced substantial CD8+ T-cell responses, as measured by IFN-g and TNF-a induction.

Vaxart also conducted a comparative experiment to compare this study data to T-cell responses from people who were vaccinated with either Moderna or Pfizer’s mRNA Covid vaccine. Data showed that Vaxart’s vaccine candidate elicited greater CD8+ T-cell responses compared to the Pfizer and Moderna jabs.

It stimulated a T cell response against SARS-Cov-2 and also demonstrated cross-reactivity against various endemic coronaviruses.

Additionally, N protein responses to SARS-CoV-1 were observed to last 17 years on infection and cross-react to SARS-CoV-2.

“The strength of T-cell responses against both S and N proteins, which we targeted, leads us to believe that VXA-CoV2-1 offers a promising solution to variants,” said Tucker.

Tucker has explained that because the Covid “S protein was likely to be highly susceptible to mutations” Vaxart decided to also include the N protein – an area “which is historically highly conserved among…coronaviruses” in its VXA-CoV2-1 vaccine. “The idea was that as the S mutated, we would still be able to elicit a strong T cell response against the N proteins” to protect against emerging variants.


Oravax’s oral vaccine candidate

In March, Oramed Pharmaceuticals, a US-based clinical-stage pharmaceutical company focused on the development of oral drug delivery systems, announced that it had entered into “definitive agreements” to form a joint venture focused on the development of novel oral Covid-19 vaccines.

The newly formed company, Oravax Medical Inc., is leveraging Oramed’s proprietary POD oral delivery technology and Indian firm Premas Biotech’s novel vaccine platform.

Oravax’s Covid-19 vaccine candidate is a virus-like particle (VLP) triple antigen vaccine that targets three structural proteins.

The company said the oral delivery of the vaccine should allow for wide-scale inoculation and easier distribution.

“An oral Covid-19 vaccine would eliminate several barriers to rapid, wide-scale distribution, potentially enabling people to take the vaccine themselves at home,” said Oramed CEO Nadav Kidron. “While ease of administration is critical today to accelerate inoculation rates, an oral vaccine could become even more valuable in the case that a Covid-19 vaccine may be recommended annually like the standard flu shot.”

In a pilot study done in animals, the oral vaccine promoted both systemic immunity through Immunoglobulin G (IgG), the most common antibody in blood and bodily fluids that protects against viral infections, and Immunoglobulin A (IgA).

Oravax expects that a clinical study will commence during the second quarter of 2021.

Orovax said its candidate being a VLP triple antigen vaccine “should make it a better candidate for protection across emerging mutations of the coronavirus”.


Intranasal vaccines

The mucosal immune system serves as the body’s first line of defence against outside pathogens at sites like the nose, mouth, eyes, lungs, and GI tract.

As the nasopharynx (the space above the soft palate at the back of the nose that connects the nose to the mouth) is the primary entry point for SARS-CoV-2, targeting the nasal cavity with a vaccine makes a lot of sense. If you can stop the virus in the nasal cavity then it won’t be able to reach the lungs where it causes the most damage.

“By generating effective mucosal immune responses, it should be possible to forestall coronavirus infection from the outset, and also more effectively reduce transmission of the virus,” Michael Russell, PhD, an emeritus professor of microbiology and immunology at the University at Buffalo in New York told MedPage Today. “Nasal immunisation aims to replicate this natural immunisation process in a more effective manner.”

The injectable vaccines currently available coax a systemic immune response by generating circulating IgG antibodies that neutralise pathogens before they can cause severe tissue damage. However, IgG is not great at repressing viral entry into the body, unlike the mucosal immune system which produces secretory IgA at the site of viral entry, and in greater volumes than any other type of immunoglobulin in the body.

Of the 96 Covid-19 vaccine candidates in clinical trials, eight are intranasal vaccines. Out of these, two are leading the race and in Phase II clinical trials.

One is being developed by the University of Hong Kong, Xiamen University, and the Beijing Wantai Biological Pharmacy Enterprise, in partnership with the Coalition for Epidemic Preparedness Innovations (CEPI) and is based on a live-attenuated influenza virus.

CEPI said it should be possible to scale the production of this vaccine candidate to hundreds of millions of doses and that the vaccine platform can be easily and rapidly adapted to target emerging variants of Covid-19.

The other is being developed by Razi Vaccine & Serum Research Institute in Iran.

The recombinant spike protein vaccine candidate dubbed Razi Cov Pars is intended to be delivered in three doses; the first two doses are injectable, and the third dose is inhaled via nasal spray. The volunteers participating in current trials are those who have gotten the first and second doses.

“The most important reason for Covid-19 spread was that a group of infected people who were carrying the virus showed no symptoms of the disease, so their respiratory system had to be secured; this inhaled dose activates the Immunoglobulin E (IgE) in the upper respiratory tract two weeks after the inhaling and prevents other people from being [infected],” head of the Razi Institute Ali Es’haqi explained to Iran Press.

“The second phase of the inhaled vaccination will be carried out on 500 volunteers in early June, and after two months, the third phase will start,” he said.

Other nasal spray vaccine candidates in clinical trials include Altimmune’s nonreplicating adenoviral vector intranasal vaccine dubbed AdCOVID in Phase I in the US; Meissa’s live-attenuated candidate also in Phase I trials in the US; Cuba’s Center for Genetic Engineering & Biotech protein subunit vaccine in Phase I/II; Codagenix/Serum Institute of India’s live-attenuated SARS CoV-2 COVI-VAC vaccine in Phase I; India’s Bharat Biotech’s BBV154 – A novel adenovirus vectored, intranasal vaccine; the University of Oxford/AstraZeneca’s Covishield, an intranasal version of its ChadOx1 vaccine in Phase I; and the inhaled version of CanSino Biologics adenovirus Type 5 Vector vaccine in Phase I/II.

Medical devices

Inovio’s Covid-19 vaccine candidate INO-4800 uses the firm’s proprietary smart device, Cellectra, to deliver the vaccine to the body’s immune system.

Also making the vaccine unique, INO-4800 is composed of an optimised DNA plasmid.

Inovio said INO-4800 is the only nucleic acid-based vaccine that is stable at room temperature for more than a year, at 37°C for more than a month and has a five-year projected shelf life at normal refrigeration temperature. The candidate does not need to be frozen during transport or storage.

With the handheld Cellectra device, DNA instructions for building the coronavirus spike protein are zapped into the skin in seconds with a pulse of electricity. Then, cells in the body produce the spike protein and cue the immune defences.

In May, Inovio announced results from its Phase II clinical trial of INO-4800 which found it to be safe, well-tolerated and produced an immune response against the virus.

The trial, which enrolled around 400 participants aged 18 and above, helped the company confirm an appropriate dose for testing in a Phase III trial.

“Our Phase II results validate our initial Covid-19 Phase I results in a larger population, which show that INO-4800 continues to be generally safe, well-tolerated and immunogenic in all studied age groups,” Inovio’s chief scientific officer Dr Laurent M. Humeau said.

In April 2021, Inovio announced results of a study that showed INO-4800 induced a robust T cell response against all spike protein variants tested, which the firm says will be key in providing protection against SARS-CoV-2 variants, in addition to providing similar levels of neutralising activity against both the UK and Brazilian variants as those against the original strain.


Patches on the horizon

In January 2021, Swansea University announced that researchers were developing the first coronavirus vaccine ‘smart-patch’.

The disposable device uses millimetre-long micro-needles (MNs) made from polycarbonate or silicon that not only can administer the vaccine but also monitor its efficacy by measuring the body’s immune response from biomarkers in the skin, according to the researchers.

The patch will be strapped or taped on to the skin to hold it in place for up to 24 hours.

The device is then scanned, providing a data reading that can be used to understand the efficacy of the vaccine and the body’s response to it.

“Skin vaccination using MNs has been described as a superior immunisation approach due to its potential to overcome immune tolerance observed in pregnancy, and lower vaccination costs through antigen dose-sparing, which is especially relevant in underserved countries,” said project lead Dr Sanjiv Sharma of Swansea University.

“The primary goal of this project is to create a prototype of smart vaccine delivery device that can not only deliver the Covid-19 vaccine transdermally but also monitor biomarkers in the skin compartment in a minimally invasive way, offering real-time information on the efficacy of the vaccination. The new method would change the way in which vaccine efficacy trials are performed from a statistical assessment to a scientific measurement of patient inflammatory response to vaccination.”

The project received Welsh Government and European funding to help in the global fight against the coronavirus pandemic. However, it is hoped that the patch can be used to treat other infectious diseases.

The researchers have said that the prototype will be developed by the end of March 2021 in the hope it can be put forward for clinical trials in partnership with Imperial College London.

Vaxess Technologies, a biotech company in Cambridge, Massachusetts, is also working on a patch that could be used to administer a combination vaccine for both COVID and the seasonal flu.

“Think of a nicotine patch for vaccines,” Vaxess Technologies CEO Michael Schrader told NBC Boston. “COVID is going to start to look a lot more like influenza, we see new strains emerging, and unfortunately our best estimation is that’s going to require seasonal boosters.”

Vaxess patch is also covered in micro-needles that barely break the skin but can deliver a vaccine after just five minutes of wear according to Schrader.

The company recently received a grant from the National Institutes of Health to develop the patch, but it has yet to be studied in clinical trials and will need FDA approval meaning that the product will likely not reach the market for a couple of years.