On The Challenges We Face In Securing Covid-19 Vaccines

The early wave of Covid-19 vaccines appear unlikely to deliver a complete shield against getting the infection, as (say) a measles inoculation comes close to providing. They seem more likely to resemble a flu vaccine. Meaning: they will reduce (but not eliminate) the risk of contracting the disease, and will also hopefully reduce the risk of experiencing severe symptoms should an infection occur. We are going to need to be realistic about what even a relatively successful vaccine can deliver. Set the expectations too high and the outcomes could easily erode public trust in the entire vaccination programme.

To repeat : if and when the first crop of Covid-19 vaccines arrive , their prime role will be to help control the spread and severity of the disease, rather than preventing infection entirely. The first entrants on the market are unlikely to be the best an final option. Ideally, as Dr Greg Poland head of Vaccine Research at the famed Mayo Clinic has indicated, it would be great if a Covid-19 vaccine could produce lasting immunity from a single dose, but that’s a long way off. Poland believes the following timeframe (lightly edited into ordinary English) is more realistic:

* A two-dose vaccine released in January 2021 for emergency use [eg by frontline medical staff] with only “moderately” high 5-10% incidence of adverse events, and effective in 60% of cases

*A two-dose vaccine released in March 2021 [also initially for frontline emergency use] with a lower rate of adverse events, and effective in 70% of cases.

*A two-dose vaccine released in April 2021 under full licensing, with an “acceptable” adverse reaction rate, and effective in 60-70% of cases

*A one-dose vaccine released some time afterward, with a very low rate of adverse events and effective in up to 90% of cases

So….the Covid-19 vaccine hunt won’t have one of those Hollywood endings where Morgan Freeman smiles wearily, switches off his Bunsen burner and says “Problem solved, throw open the borders!” There will be fine-tuning required.. Some vaccines will be found to work better with fewer side effects, depending on age, gender and ethnicity. Also, achieving a safe and reasonably effective Covid-19 vaccine formulation will be just the beginning. We also need to be considering :

(a) how to manufacture or import the vaccine under licence on a mass scale via supply chains negotiated jointly with other countries, and/or with the vaccine providers

(b) how to refrigerate and transport the vaccine in a stable state for weeks in the minus 70 degree conditions that some of the vaccine contenders currently require and

(c) how to acquire sufficient quantities of the medicinal glass vials and stoppers to store and administer the vaccine safely, efficiently, and equitably.

This likelihood that ‘first will not be best” also has implications for political management. On recent performance, it will be a difficult for government to convince the media, the business sector, the Opposition and an anxious public that waiting for a better vaccine ls desirable – and that this delay hasn’t been due to a government failure to win New Zealand a higher place in the global queue. In the face of a global pandemic, preaching the virtues of deferred gratification is going to be a hard sell.

Small, perfectly formed vaccines

Last Thursday, a visit to the Malaghan Centre at Victoria University gave PM Jacinda Ardern and Research, Science and Innovation Minister Meghan Woods an opportunity to update themselves – and the wider public - about New Zealand’s current state of vaccine readiness. Our vaccine preparedness strategy was kicked off by the $37 million investment announced in May. The strategy is being managed by a task force led by MBIE and the Health Ministry, and includes other purchasing and regulatory agencies. .

On Thursday, Ardern and MBIE‘s Dr Peter Crabtree confirmed that the government is engaged with all of the leading vaccine providers both directly, and through our participation in various international and local vaccine alliances. New Zealand is also having discussions with other countries that are already setting up advanced purchasing arrangements with some of the vaccine providers deemed most likely to succeed. Ensuring supply for New Zealand will involve a degree of piggy backing on ( and supporting) the huge pre-order commitments that Australia, the US, the UK and Europe have been making over the past couple of months. (There was global pushback against early attempts by the Trump administration to monopolise vaccine supply for Americans.)

One aim of the early purchasing deals has been to secure supply at an affordable price per dose The measures in train have included:

1. Diplomacy. On Thursday, Ardern mentioned that she been talking about vaccine prospects and access issues (including presumably, a consistent regulatory approach) with Angela Merkel, Justin Trudeau and Scott Morrison
2. Negotiating as mentioned, with the pharmaceutical companies involved in vaccine creation and trialling and with those governments engaged in pre-ordering between 100 million doses from the likes of Astra Zeneca (as Australia has done) and the 300 million doses from Astra Zeneca reportedly ordered by the United States.
3. Donating to the international vaccine distributing organisations here and abroad ( eg the GAVI Alliance) that are trying to establish a fair and equitable global system of access to Covid-19 vaccines
4. Funding the local capacity for large scale vaccine manufacture and delivery
5. Funding promising local vaccine makers, so that we can contribute to the global array of effective vaccines. Ultimately, there will be about 9 billion potential customers for such vaccines. We know already that infection rates and outcomes differ according to age, gender and ethnicity. Those variations allow for targeted vaccines to be developed, in accord with national characteristics. In the medium to long term, there looks like being plenty of room ( and potential for profit) for niche contributions.

Clearly. a small country like New Zealand can’t afford to buy its way up the queue for a successful Covid-19 vaccine. We can’t match the purchasing power of the United States. Our main bargaining chip has to be that in the context of this global pandemic, we’ve earned a few brownie points by being a good global citizen – as demonstrated by how we’ve contributed funds and expertise to the international effort to combat this virus. Here’s an update on some of the key challenges :

1.Who are the leading contenders? As mentioned, testing for safety and efficacy will need to be carried out amongst human groups large enough and diverse enough (in age, gender, and ethnicity ) to pick up any significant side effects. For any vaccines that pass such tests, the initial challenge will be to gear up the resources required to make hundreds of millions of doses. Hopefully, the fact there are scores of contenders at various states of readiness will spread that effort.

The leading group – judged by results to date, and progress towards wide-ranging human trials are (a) the Astra Zeneca’s vaccine being developed in conjunction with scientists at Oxford University (b) the Moderna vaccine being developed with the National Institute of Allergy and Infectious Diseases (c) the Pfizer vaccine being developed with the German firm BioNTech and (d) the Johnson and Johnson vaccine being developed via J&J’s Janssen Pharmaceuticals subsidiary.

2.What are the differences between them? The 100 or so Covid-19 vaccines in development come in all types, and in variations within each of those types. There are the“inactivated virus” vaccines (eg the Johnson and Johnson effort) the “viral vector” vaccines ( eg Astra Zeneca, which is using a tweaked version of a chimpanzee-derived common “ adenovirus” as a delivery vehicle) and thirdly , the “mRNA/ DNA” vaccines being pioneered by Moderna and Pfizer.

To convey some idea of the complexity involved…reportedly, Johnson and Johnson delivers the SARS-CoV-2 spike protein into cells using an inactivated common cold virus as the delivery vehicle. That prompts the immune system to launch a counter attack against COVID-19. J&J is currently developing seven vaccine candidates, each of which involves the expression of a different variant of the spike protein.

In practice, all of the various delivery platforms share the common aim of triggering the body’s immune system to recognise and attack any intruder resembling the virus responsible for Covid-19 - such that (later) when the real virus arrives, the immune system has made antibodies ready for deployment against the intruder. Just how enduring the protection/mitigation effects of these antibodies will be is currently a bit of an unknown. In recent days, there have been disturbing reports from Hong Kong of Covid-119 re-infection occurring, only a few months down the track. Scarily, this would suggest that the antibodies may offer protection for only a brief period of time. Obviously, this would limit the effectiveness of any vaccine.

Footnote: By way of historical comparison, Albert Sabin’s famous oral polio vaccine of the 1950s relied on an “attenuated” virus as a vehicle, while Jonas Salk’s polio vaccine used a “de-activated” form of the virus. By modern standards, both were relatively difficult to manufacture and to store in large, stable quantities. Back then, they also carried a (limited) risk of reverting to an active form of the virus.

3. Is anyone potentially unable to take the vaccines? The Covid-19 vaccine contenders rely on deliberately stimulating the body’s immune system to combat the virus. This could therefore be problematic for those with pre-existing medical conditions that require medications that suppress the immune system. Malaghan Centre scientists spoken to for this article confirmed that people reliant on immunosuppressants will probably need to wait for “ herd immunity” to develop within the wider population at say, a 95% rate of Covid-19 vaccination. /

Advice on the management of immunosuppressants and Covid-19 infection can be found here. A study in the Lancet (based on 2020 research conducted in Italy) concluded that advanced age and pre-existing medical conditions were more significantly linked to poor outcomes from Covid-19 than the taking of immunosuppressants per se.

4.What is the likely cost for dose? At this point, everyone can only speculate about the likely costs per dose. If and when a Covid-19 vaccine arrives, it will almost certainly be restricted at first to frontline medical staff. When made more widely available, it could be offered free via the public health system, as the Morrision government has already promised to Australians, and as the Trump administration has promised to Americans. Obviously, taxpayers will eventually be picking up the tab for these political acts of generosity, via taxation.

Still, the current projected costs per dose emanating from the leading vaccine contenders do give a useful ballpark indication for government purchasing agents, such as Pharmac. Cost will be one factor in the access and licensing negotiations we have with Australia – and will also be a consideration as Canberra and Wellington construct a vaccine supply chain within the Pacific region.

In no particular order. Johnson and Johnson is offering its vaccine at $US10 a dose within the context of a100 million dose contract. Details of the huge pre-order deals that the US and UK governments have made for the Pfizer/BioNTech vaccine can be found here. At present, Moderna is reportedly charging between $US32and $US37 per dose for its candidate. Sinopham , the state-owned Chinese pharmaceutical company. is reportedly pitching the cost of its vaccine at up to $US145 for the two shots required.

As mentioned, the Astra Zeneca vaccine is the candidate most likely to be the first entrant in New Zealand. Stage three trials are being conducted in Brazil, South Africa and the United Kingdom. Australia has (tentatively) put a 100 million dose purchase order in place with Astra Zeneca. The 300 million dose pre-order deal that Astra Zeneca has struck with the US government roughly translates to a price of $US4 per dose but that estimate may rise, given that the $1.2 billion bulk sum being cited also includes an undisclosed figure for clinical development.

Clearly what this underlines is that cost control will definitely require New Zealand to attach itself to the large pre-orders being placed by other countries. It is doing so with Australia over access to the Astra Zeneca vaccine, and we will presumably add our weight to Australia’s access deals with the other contenders as well, as these develop. On that score, it would be interesting to know if Ardern’s recent talks with Angela Merkel included possible access to the vaccine that Pfizer is developing with the German firm BioNTech.

5.Can we adequately refrigerate these vaccines? If we’re serious about our Vaccine Preparedness Strategy, the plan will need to consider how to go about creating an unbroken ‘cold chain’ from the site of importation/manufacture right on through to the point of vaccination. Efficient refrigeration is going to be crucial to preserving the vaccine’s potency, and to avoiding wastage : “

The World Health Organization estimates that up to 50% of vaccines are wasted globally every year; a large part because of lack of temperature control and the logistics to support an unbroken cold-chain. At the scale of COVID-19, this spoilage rate could waste potentially a billion vaccines, which, even if valued at a non-profit cost of around $10 a vaccine, represents a staggering wasted investment.

Relevant point being, RNA is highly unstable. So if the mRNA/DNA vaccine type proves to the safest and most effective vaccine, the need for portable refrigeration will become even more acute. Last Thursday I mentioned to Malaghan Centre director Graham Le Gross, that achieving effective refrigeration will pose a delivery problem for the likes of Africa and India. And here as well, Le Gros ruefully replied, given that our public health system doesn’t have much in the way of minus 70 degree capacity readily at hand. .

6. And what about the medicinal glass? We’re talking about three hundred million Covid-19 vaccine doses for the US alone, and between three and five million doses for New Zealanders. Those numbers appear bound to create a worldwide shortage of medicinal glass, and will compound the pre-pandemic shortage of the silica essential to glass making. Any Vaccine Preparedness Strategy will require us to secure either overseas supply (or the ability to locally manufacture ) the glass vials and stoppers cehtral to the delivery of any large scale vaccine programme. The risk is that medicinal glass could become a significant bottleneck (no pun intended) in the global vaccine effort. This problem can only be partially mitigated by storing multiple vaccine doses in a single vial.

7. What about the IP? Right now, the global effort to combat the coronavirus has seen a remarkable level of collegial joint effort and the free sharing of research findings and trial outcomes. Yet at some point, the pharmaceutical companies (and countries) engaged in the development of new vaccines (and this includes the re-purposing of existing patented medicines) will be looking to recoup some of their investment. Efforts to patent and licence Covid-19 related medical innovations seem inevitable. The question will then arise as what parts of the various technology platforms and gene sequencing techniques can legitimately be patented, and on what grounds.

If New Zealand seeks to build a capacity here to manufacture vaccines, this would (presumably at first) be under licence, from patent holders located elsewhere. If we did succeed in making a significant contributions to the development of our own Covid-19 vaccines or medical treatments, this might well – for instance - involve the use of genetic sequences in whole or chopped parts, derived from humans or other primates, or created synthetically. Given the size and value of the potential market, the legal environment for Covid-19 vaccines and medical treatments will encourage fierce competition. Membership of those international vaccine alliances may offer us some protection even if we eventually do need to amend our domestic law in line with the rules such alliances may establish.

In April Victoria University professor Susy Frankel ( a property law expert) gave a brief overviews of the patent situation with respect to pandemic medicines and vaccines. Frankel’s contribution kicks in around the 20 minute mark here . As we move closer to the specifics of what can (and cannot) be patented in the area of genetic manipulation….it is widely agreed that human life and genetic sequences drawn from it cannot be patented.

To that end, the landmark 2015 case D’Arcy v Myriad Genetics has provided a useful preview of issues likely to resurface with respect to Covid-19 vaccines and treatments. Briefly, D’Arcy argued that the isolated nucleic acids central to Myriad’s patent were not significantly different from cellular nucleic acid. Even in isolated form, D’Arcy argued, naturally occurring DNA and RNA are products of nature, and therefore cannot form the basis of a valid patent.

Myriad responded that their unique isolating technique had created “a new and useful effect of economic significance, and that the isolated nucleic acid differed from the nucleic acid found in a human cell chemically, structurally and functionally.” Regardless, D’Arcy won, thereby preventing private companies ( for a time at least) from gaining a virtual monopoly on some elements derived from human nature. Arguably, any other result could have a serious chilling effect on research vital for public health purposes.

Fine. But what about situations where the material is being manufactured and manipulated by techniques that result in synthetic outcomes that are significantly detached from nature ? Arguably this could be the case in the new, chopped sequences and related techniques central to the mRNA/DNA vying as Covid-19 vaccine contenders.

Obviously, this territory is open to challenge. In the US case Association for Molecular Pathology v Myriad Genetics, the Court ruled that synthetically created cDNA is patentable, while also maintaining the earlier position that isolated natural DNA is not. So far, New Zealand patent law hasn’t really had to grapple with some of the issues inherent with the new vaccines. It will need to do so if and when this country embarks on building its own Covid-19 manufacturing capability. This will be regardless of whether we import Covid-19 vaccines under licence, or whether we create them here via our own scientific efforts. If we do successfully create new vaccines here, we will obviously want them to have IP protection. Yet some such work may to some degree, be building on existing techniques that may in future become subject to a patent claim. There isn’t a clear road ahead.

Footnote: If you have the time and inclination to go down a legal rabbit hole as to how prior patent rulings – concerning a firm called Arbutus - have cast a patenting shadow over Moderna’s Covid-19 vaccine contender, then be my guest.

8. Future Prospects

Finally, what should we expect once the first Covid-19 vaccine stage three trial results begin to emerge over the next few months? According to the US pharmaceutical researcher and analyst Derek Lowe we’re quite likely to see a patchwork quilt of results:

What if [we have]Vaccine A being pretty good, but not in older patients, while Vaccine B seems better in that cohort but is harder to roll out for distribution, while Vaccine C showed more even results over various patient cohorts but is beaten by some other candidate in any particular one, while Vaccine D was strong but definitely had more adverse events. . .I can easily imagine something like this happening, and the thing is, it’s not just going to drop all at once. We’re going to get those various results one after the other and will have to fit them into an unavoidably messy picture, adjusting our plans as more data points become available.

Right. And will the government bow to the pressure to buy them all, whatever the cost? Lets hope not. Lets hope we can have a rational public debate about how best to allocate our limited resources, in order to secure the Covid-19 vaccine(s) that offer the widest benefits to the most people, with the fewest number of serious side effects. But as Lowe says, “wait and see” isn’t exactly the zeitgeist mood right now.

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