This month, we got news that another couple of next generation vaccines are heading into human trials, both with national research agency…
We don’t know how many groups started out with the goal of creating a patent-free or non-profit Covid vaccine – or at least something close to that. We know of at least one that couldn’t overcome the hurdles very early on, and that story underscores what an uphill battle it is. That was in Finland.
Back in May 2020, a group led by Kalle Saksela had developed a Covid vaccine nasal spray that they wanted to be “the Linux of vaccines” – a truly free global good, like the iconic open source computer operating system. Soon after, they got a public agency grant of over a million Euros to develop it. In March 2021, the group announced that preclinical studies had gone well and they were ready for clinical trials. But the team couldn’t get the funding needed for those, so it went no further. As far as I can tell, the preclinical studies and open details of the vaccine were never published.
Over in Texas, meanwhile, Peter Hotez and Maria Bottazzi were facing the same struggles, but managed to get more funding. In May 2020 they got a million dollars from the philanthropic arm of Tito’s Handmade Vodka – and they ultimately pulled together a further $6m, from mostly private sources. The clinical trials for their vaccine would be run by an Indian pharma company the group had worked with before, with support from CEPI and BIRAC, an Indian public agency. That company planned to manufacture the vaccine cheaply if it cleared all the hurdles to come – which it did. More on that vaccine, Corbevax, soon.
It sounds simple – non-profit, and no patent (or a patent waiver). It’s not, though. And there are many layers that affect how accessible a vaccine will be. For example, needing only technical capacity and ingredients that are already widely available globally is critical to achieving a major supply of affordable and effective vaccine. And making optimal and economical use of global vaccine manufacturing capacity would, in itself, increase access – we need all hands on deck.
Then there are other attributes needed for affordability, like ease of distribution and vaccination – think here of the huge hurdle created by the expensive logistics of keeping current mRNA vaccines super-frozen. As well as developing vaccines that don’t have those hurdles, there are other ways to bypass them or at least reduce their cost. For example, from later this year the Institut de Pasteur in Dakar, Sénégal will be packaging Covid vaccines into pouches, similar to IV bags in hospitals, instead of glass vials. Reducing the size and weight of what has to be transported reduces the cost of the vaccine cold chain.
This map is important to keep in mind as we go into these stories, too:
That map is not just a reminder of how dramatic the global shortfall of vaccine is – made even more precipitous knowing that full vaccination is essentially 3 doses (see my previous post), with more boosters on the cards for the longterm. It’s also a critical perspective to keep in mind for the logistics of clinical trials for new vaccines.
In 2020, one of the big hurdles the frontrunner vaccines had to face was managing to have enough trial participants ready and waiting in just the places that outbreaks would roll over them – something that required both good management and luck. Setting up trials takes a lot of time, and you couldn’t predict where the lightning was going to strike. I wrote about that challenge at WIRED.
Now there’s no shortage of outbreaks, unfortunately, but there’s another issue: how do you get enough unvaccinated people to run a big phase 3 trial when pretty much everyone who is both easy enough to reach and wants to be vaccinated already is vaccinated? Here’s hoping that there have been conversations with the WHO SOLIDARITY trial for vaccines about this.
That’s a big phase 3 trial with a shared placebo group to test 4 easy-to-distribute and scale up vaccines. As of the middle of December, 5,000 people had already been recruited in the Philippines alone. There are 2 vaccines already in the trial – a protein subunit vaccine from Medigen (Taiwan) and a DNA vaccine from Inovio (USA). The next 2 candidates are the self-amplifying RNA vaccine from Arcturus (USA) and a live attenuated vaccine from Codagenix (USA – to be manufactured by the Serum Institute of India). More vaccines could be added, though.
Now on to the non-profit vaccine news. As far as I know, here are the vaccines that are non-profit, or very close to it:
- Already rolled out – with limits on non-profit use: AZ, J&J, and Cuban vaccines
- An authorization for a patent-free vaccine: Corbevax
- In suspense: the NDV-HXP-S vaccine quartet
- The one that struggled: Imperial College London and saRNA (Covac1)
Rolled out – with limits on non-profit use: AZ, J&J, and Cuban vaccines
AstraZeneca (AZ) / Covishield
This vaccine is the fourth most widely used vaccine globally. According to the latest estimates from the UK, by 6 months 2 doses of this vaccine don’t protect against getting sick from Omicron, and there’s low (25-35%) effectiveness against hospitalization (UK Health Security Agency, January 27, 2022) – a problem facing other vaccines, as well. However, protection can be higher than it was after the second dose with a third shot of another vaccine – or when AZ is a booster for another vaccine (see my previous post for details).
Limits on its non-profit use? It’s never been straightforward. AZ licensed the vaccine from Vaccitech, the for-profit company set up by the vax developers and Oxford University. Although there has been a commitment from AstraZeneca to add no profit margin for themselves during the pandemic, the Covishield version that’s widely used isn’t produced by them: it’s produced by the Serum Institute of India (SII). SII does make a small profit on it (and reportedly a large profit on sales to private hospitals in India). SII was reportedly India’s most profitable large company in 2021. The cost of the SII version for African countries is nevertheless at the very low end for Covid vaccine – about the same as Novavax, and similar to a price reported for CanSino’s single-shot vaccine. I haven’t seen reports of the arrangements with the other manufacturers of this vaccine globally (including CSL in Australia).
For AZ, the vaccine’s sales haven’t fully covered the costs of the vaccine. From 2022, though, they aim to make what they describe as a modest profit – but not in poorer countries, where pricing won’t change. It’s not yet clear what will happen to the price of Covishield.
According to a list maintained by Knowledge Ecology International (KEI) – which looks reasonably correct, but a bit out-of-date to me – Oxford University and/or AZ has more agreements for local partial or full manufacture than any of the other non-profit vaccines in this post; though none in Africa.
The J&J vaccine is the ninth most widely used Covid vaccine in the world. With 2 doses, the vaccine provides very high protection against severe Covid outcomes, and can also be effective as a booster for other vaccines. After a second dose, this vaccine came in at around 75% efficacy against symptomatic disease globally (90% in the US), with no severe or critical outcomes in people vaxed in the 2-dose trial. (For more details, see my recent post.)
Limits on its non-profit use? There haven’t been any, except for a time limitation – “for emergency pandemic use“. It’s not yet clear when that will be. There’s a report it could be as late as the end of 2022/early 2023, but I don’t think the company has released a timeframe. In November, the company announced that they had signed a deal with COVAX to provide the vax for its Humanitarian Buffer. The Buffer is a project to try to protect people who won’t necessarily be looked after by governments – for example, people in war zones or areas that aren’t controlled by governments.
According to the KEI list, this is the only not-for-profit vaccine with a manufacturing arrangement on the African continent (with Aspen pharma). However, the vaccines finished there were shipped out of the country. At the end of November, though, Aspen announced it was on the cusp of a deal to sell their product in Africa in November – they plan to call it Aspenovax.
Cuban vaccines – Abdala, Mambisa, and Soberana (1, 2, and Plus)
Cuba’s suite of locally-developed protein subunit vaccines are very effective after their 3-dose courses, and the country is deep into a roll-out of its first booster – the fourth dose. (For more details, see my recent post.)
The Cuban biopharma sector is government-owned, and 2 institutions developed Covid vaccines: the Finlay Institute of Vaccines (IFV) and the Centre for Genetic Engineering and Biotechnology (CIGB). Finlay produced the Soberana group of vaccines (Soberana 1, Soberana 2, and Soberana Plus). CIGB produced Abdala and Mambisa. All are protein subunit vaccines – Soberana 2 is also a conjugate vaccine (the Covid-specific part is joined with tetanus toxoid to strengthen the immune response). Mambisa is a nasal vaccine.
Results are available for the phase 3 trial in Cuba for the main vaccine schedule: 2 doses of Soberana 2, with a third of Soberana Plus. Vaccine efficacy was 92.4% (CI 87–96). (Adding that additional vaccine/dose to the mix bumped efficacy up from 71% for 2 doses of the same vaccine.) In the phase 3 trial in Iran, vaccine efficacy of 91.7% (CI 21-99) was reported (including on the Finlay Institute’s blog), but results aren’t published yet. CIGB announced a vaccine efficacy rate of 92.3% for Abdala, but no further data is publicly available. (My summary from last year is here.) I haven’t been able to find any clinical trial data for Mambisa.
The limitation on being non-profit here is a very big one: the vaccines are only not-for-profit domestically. And biotechnology is, according to the WHO, “one of Cuba’s largest sources of foreign exchange”. But it’s an important example of what domestic production can achieve. Cuba is one of the most Covid-vaccinated countries in the world: in January 2022, more than 93% of the population had at least 1 dose of locally-produced vaccine, with deaths per million population below the global average.
Protein subunit vaccines only need ordinary fridges and vaccine distribution, and the technical capacity to manufacture them is widespread. Details of the arrangements being made internationally for Cuban vaccines aren’t public, as far as I can see. Soberana is also used in Iran, which partnered with the Cuban developers, the Finlay Institute, to run trials and manufacture the vaccine locally. Other countries using Cuban vaccine: Mexico, Nicaragua, Syria, and Vietnam. A year ago, a partnership with Ghana to manufacture Soberana there was announced – but that’s gone quiet, so it’s not clear if that’s going ahead. (Soberana hasn’t been listed by the drug regulator as authorized for use in Ghana, which isn’t an encouraging sign.)
An authorization for a patent-free vaccine: Corbevax
This is the vaccine from Texas discussed earlier, from Baylor College of Medicine and the vaccine center at Texas Children’s Hospital. And the limitations on this are so minor, that it appears to be the cheapest Covid vaccine on the market by a long way. Reports have put the cost at $1.50 or $2.50 a dose, which means it could be less than half the cost of the AZ vaccine. It’s not patented and the developers have no financial stake – it’s not privately commercialized, as with the Oxford/AZ vaccine, and the developers are committed to providing technology transfer for free. However, the university does charge a license. The one place where it is being manufactured (by Biological E) and is authorized for use, India, is using a patented adjuvant from Dynavax in the formulation, and that’s been used in some of the studies by the US developers as well.
The big catch here is we have no idea how effective the vaccine is. Neither the manufacturers nor Indian drug regulators have released any data on the efficacy of Corbevax, and none on any phase clinical trial. Biological E’s press release reports that the trial achieved better levels of neutralizing antibodies than Covishield (the Indian-produced AZ vaccine). Because only measures of immune response were tested, even when the clinical trial data is reported we won’t really know how effective the vaccine is until it’s rolled out and effectiveness studies are done.
When the phase 3 trial for Corbevax started, Biological E’s press release said, “It is intended to be part of a larger global Phase III study”. I haven’t seen any discussion of why that apparently fell by the wayside.
In suspense: the NDV-HXP-S vaccine quartet
This one is at a nail-biting stage. As I wrote last year, it couples old school, widely accessible technology – the vaccine can be mass-produced in eggs the way flu vaccines are – with a major advance in the way the virus spike is modified.
This a viral vector vaccine, based on the Newcastle Disease virus (NDV) and the Hexapro spike (HXP-S), which is a modification of the spike protein that could make this vaccine particularly potent. A license from the University of Texas at Austin developers of HXP-S is available to low and middle countries without royalties, and the Mt-Sinai-developed NDV platform is also non-profit. There’s a must-read article on this vaccine by Carl Zimmer in the New York Times.
- Brazil: with the Butantan Institute, for the injected vaccine, Butanvac;
- Mexico: with the pharmaceutical company, Avimex, for a live nasal version, Patria;
- Thailand: with the Government Pharmaceutical Organization (GPO), for the injected vaccine, GPOVac;
- Vietnam: with the Institute of Vaccines and Medical Biologicals (IVAC), for the injected vaccine, CovIVAC.
Back in November 2020, it was estimated that the original trio (minus Mexico) could manufacture half a billion doses annually between them.
Thailand was the first group to get as far as registering a clinical trial, and there are clinical trials now in all 4 countries, as well as a phase 1 trial recently registered by the US group themselves. The results from the phase 1 trial of GPOVac in Thailand (using the same Dynavax adjuvant as Corbevax) were released in September 2021. And results of blood tests for some of those participants were released a few days ago, with the researchers concluding the measures of immune response were comparable to those of people who had the Pfizer vaccine.
The reason for the suspense? Phase 3 trials. In Vietnam, phase 1/2 results were reported a few days ago. The vaccine got over the bar that had been set to justify a phase 3 trial – signs of immune response were higher than those of the AZ vaccine, to which it had been compared. It’s reportedly not proceeding though. That possibility was already being discussed a few weeks ago, because vaccination rates are so high in Vietnam a phase 3 trial might not be feasible there.
In Brazil last August, Butantan switched from a placebo-controlled phase 2 trial to a CoronaVac comparator group because of the difficulty of recruiting people. That’s a very large trial – over 5,000 participants. Early in January, there was a media report suggesting that phase 2 hadn’t started yet, and questioning whether recruitment would be feasible there. The phase 2 trial for Patria is still recruiting in Mexico.
So, all eyes on Thailand: they plan on a 4,000-participant phase 3 trial, acknowledging, however, that recruitment is going to be a tough challenge.
With fingers very tightly crossed…
The one that struggled: Imperial College London and saRNA (Covac1)
This one started with a very ambitious goal: a publicly funded development effort which aimed to sidestep the drug industry and forego all licensing fees as well as profits. It’s a self-amplifying RNA (saRNA) vaccine from Imperial College in London. In a preclinical study, it induced more immune response than the AZ vaccine.
The group started down the human challenge trial road, as well. The first volunteers in their early tests to establish human challenge methods left quarantine, and that was followed by a 90-person study to determine the minimum amount of virus needed to infect someone – all prerequisites for running a human challenge for vaccine efficacy, which wouldn’t answer safety questions, but would bypass the need for a very large phase 3 trial for efficacy for low-risk people.
Their first clinical trial was a traditional phase 1 trial, but the results were less than hoped for: low doses could induce immune responses, though not enough. They planned to modify it before going further. That was in June 2021.
In September, Imperial College announced “a strategic long-term research collaboration” with AstraZeneca for development and commercial application of their saRNA technology through a spin-off company, VaxEquity. That includes Covac1, and the goal of the “widest possible global population at low cost, including for low- and middle-income countries”.
Their announcement included a good explanation of saRNA: it is “based on temporary genetic code, called messenger RNA, which can be used to train the immune system to recognise and respond to threats, such as a virus…[O]nce injected into muscle, the RNA message makes copies of itself (‘self amplifies’), generating more of the original message. This means it can produce consistent and strong immune responses at a fraction of the dose of other RNA vaccines”. A fraction of the dose drives down cost, too. While the original non-profit goal is apparently now out of reach, there are many paths to an affordable vaccine, and this vaccine is still heading down one.
Disclosures: My interest in Covid-19 vaccine trials is as a person worried about the virus, as my son is immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.
The cartoons are my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.) If you’re not familiar with the inspiration behind the head cartoon at this post, it’s a folktale for children on optimism and hard work called “The Little Engine That Could” – in its quest to haul toys and food up a mountain to reach children who need them, it chugs and puffs its way uphill, saying “I think I can, I think I can, I think I can….”
The world map of vaccines is under a CC BY 4.0 license from Our World in Data: Hannah Ritchie, Edouard Mathieu, Lucas Rodés-Guirao, Cameron Appel, Charlie Giattino, Esteban Ortiz-Ospina, Joe Hasell, Bobbie Macdonald, Diana Beltekian and Max Roser (2020) – “Coronavirus Pandemic (COVID-19)”.