Thursday, October 01, 2020

When Can We Expect a Working Covid Vaccine?


From the source: "The figure above includes 10 vaccine candidates already in Phase I, 4 candidates in combined Phase I/II trials, 2 candidates in Phase II and 3Candidates in Phase II/III (Moderna is already for a total of 18 candidates in clinical phases."

by Thomas Neuburger

The fastest vaccine ever developed was the mumps vaccine, and it took four years: "The invention of the modern mumps vaccine is the stuff of medical textbook legend. In 1963, a star researcher at the pharmaceutical company Merck took a swab of his own daughter’s throat to begin cultivating a weakened form of the mumps virus. And just four years later, in record time, Merck licensed Mumpsvax as the world’s first effective vaccine against this common and contagious childhood illness."

National Geographic agrees: "The mumps vaccine—considered the fastest ever approved—took four years to go from collecting viral samples to licensing a drug in 1967."

Covid vaccine development has already started, obviously, and is racing forward at breakneck speed. Hopes are great that a vaccine will be available by the middle of next year if not sooner.

But consider this, from an excellent summary by immunologist Ignacio Moreno Echanove, of what vaccine development actually entails (italicized emphasis mine):
Regarding clinical trials, Phase I is a safeguard trial done with a few individuals (10-20) to check that the [vaccine] candidate is safe enough for trials with more volunteers. Being in a hurry, some candidates are running directly with so-called Phase I/II trials. So far, such acceleration has not been seen as problematic. So far.

The objective of Phase II (about 100 to few hundreds of subjects) is to characterize the immune response that the vaccine provides and decide if it looks good enough to proceed with Phase III.

Before starting Phase III all considerations about safe manufacturing and scaling up should/must have been settled (I wonder if this was the problem with delays in Moderna vaccine Phase III, but if so, they have just resumed to Phase III).

Phase III (many thousands on subjects, the larger the trial, the shorter the duration, but also depending on the rate of spread when and where the trial starts). Some selection of racial and age cohorts will be necessary given the known information. Phase III is to assess the efficacy of the vaccine, so during Phase III both, placebo and vaccinated subjects, will be naturally challenged in the normal epidemic evolution and tested to see how the vaccine provides immunity/protection against the vaccine. Forced challenging (as in deliberate exposure to Covid-19) has been proposed to accelerate development. ...

Phase IV studies (after approval) are basically safety evaluation studies and should be mandatory for Covid-19 vaccines given the uncertainties mentioned. Pre-exposure cohort studies or secondary attack-rate studies will also be needed given the high attack rate of Covid-19.
"Naturally challenged" means the participant is vaccinated and then exposed to a natural environment in which Covid may be present or absent. "Forced challenging" is far more aggressive. It means deliberately exposing the participants, including those on the placebo arm of a trial, to the virus itself, and therefore, and deliberately, to risk of death.

Of this the writer says, "This proposal is the subject of bioethical questions with no easy answer." Indeed.

The Vaccine-Creation Process

About the timing of deployable vaccine, Echanove notes (bolded emphasis added):
Given that this is a new and rapidly spreading disease, efficacy testing Phase III trials should be large. Somewhere between 10.000-50.000 individuals and the follow-up would take 1-2 years though some conclusions on efficacy might be obtained in about a year. If some kind of protection is seen it is crucial to check the duration. So, if at least a 6-month duration of protection –before and in case a booster vaccination is seen as necessary after 6 months or later– is a pre-requisite for approval this means that first results won’t be seen until about one year after the start of Phase III trials.

Recruiting volunteers, vaccinating them, time to full development of immune response, challenging of subjects through the natural course of the epidemic, more than 6 months monitoring after immune response, and all the work associated mean that 1 year is a bare minimum for results [after the start of large Phase III trials].
One year after Phase III trials starts is the bare minimum for results, and I would consider that optimistic in the extreme. Manufacturing and deploying a safely produced product will add to that estimate.

Given this schedule and given that the furthest-along candidates began Phase III trials this summer, I wouldn't not be optimistic about seeing a deployable vaccine earlier than 2022 — and that's if we get lucky. If undue speed in development results in an ultimately unsafe but deployed product, the entire exercise is set back. 
(Update: But pay attention to news about the Moderna candidate, listed below.)

Which Candidates Are Furthest Along?

How far along are vaccine developers? According to Echanove, these are the candidates furthest along, but they're not necessarily the most promising:

• "The University of Oxford-AstraZeneca candidate (AXD 1222, UK, Adenovirus vector) was first to announce a Phase II/III trial in May 22nd with about 10.000 volunteers in the UK, and including small children/elder cohorts. It is said to be expanded with trials in Brazil, South Africa and the US with now more raging epidemics. It had already showed preclinical results Rhesus macaques and additional preclinical trials are ongoing.

"This project also aims to soon start controversial challenge trials in which healthy participants, vaccinated or not, will be ‘artificially’ challenged with SARS CoV 2. This might accelerate efficiency results but also rises serious concerns about safety issues that could backfire later. Australian commenter Hilda Bastian highlights that this also increases what she calls the “activism risk factor” or vulnerability to deliberate doubt- sowing on vaccines. I strongly recommend reading her posts in full."

"Despite its advanced state of development, this is not a good candidate: "Moreover, given that 3 out of 6 macaques vaccinated with this candidate and then challenged with SARS CoV 2 showed symptoms of respiratory distress one wonders if this could be the best candidate to try forced challenging with human subjects."

• "The Wuhan IBP-Sinopharm CNBG is a 100% public project (China, Inactivated virus) that in June 23rd announced start of Phase III in the UAE, and has undergone mandatory preclinical studies given it contains virus."

• "Similarly, SinoVac Life Sciences (China, inactivated vaccine) has published preclinical results, has ongoing Phase I/II trials and planned to start Phase III in Brazil in July with nearly 9,000 participants according to NIH site for this trial with results expected in October 2021."

• "Moderna candidate (mRNA-1273, US, mRNA vaccine) is set to start Phase III trials on July 27th with 30.000 participants. No preclinical studies done or planned."

• "CasSinoBIO (Ad5-nCoV, China, adenovirus vector) has undergone Phase I/II trials and in 29th June was announced it had received “military specially-needed approval” and this means approval limited to military use in China for at least one year. They announced on July 11th talks for Phase III trials with Brazil, Russia, Chile and KSA and expect to enrol about 40.000 subjects."

• "The Pfizer-BioNtech (BNT 162, Germany, mRNA) candidate has just published Phase I/II results with one of their variant candidates (1b) and has also showed preclinical results. The developers plan to start Phase III later in the summer enrolling about 30.000 subjects in the US. BioNTech CEO believes [t]hat BNT162 could be ready for approval by the end of the year. As I see this, the 6-month protective duration prerequisite could only be fulfilled if Phase I/II subjects are ‘artificially’ challenged later in the year."

While the situation might look promising, it might also only look fast, perhaps dangerously so. The author notes: "One wonders if this is the result of rational thinking or if we are running all candidates into Phase III trials like a run of beheaded chickens. Time will have a say on this."

Trading Lives for Lives?

People are understandably anxious about a vaccine for this global pandemic, just as they were anxious about a vaccine for mumps. Because the death rate from mumps was about 1 in 10,000, that vaccine was developed in an orderly fashion, with all precautions and checks duly observed.

The CDC estimates the death rate from Covid-19 at about 0.2%, or 2 in 1,000 — twenty times the fatality rate of the mumps. That increase increases the call for rapid vaccine development, especially in a globally connected world, a world connected by communications, by interdependence, and by the widespread need for travel.

Will that sense of urgency cause vaccine developers and those charged with approving them to put participants at unnecessary risk in accelerated clinical trials — and then put the first population to receive the manufactured product at further risk — especially since the immunology of this disease is still not well understood?

Will the medical organizations of the world, like WHO and the CDC, be willing to trade the anticipated loss of life due to over-aggressive trials and premature deployment for other, later lives (and political careers) ultimately saved — a kind of trolley-car problem math in which one person's daughter is deliberately endangered so that two or three daughters later may live?

Echoing our writer: Time will surely have a say on this.

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At 12:04 PM, Anonymous Anonymous said...

Be careful that your biases don't politicize science. You start with the fastest vaccine developed in 1963 and base doubts off of that. Bad start. DNA sequencing didn't even start until the 1970s. Immunology, molecular biology & medicine have advanced orders of magnitudes since 1963 and needs to be factored into today's assessment of a vaccine timeline. If a vaccine is doable it will happen before 2022. Dr. Fauci explains "““With all due respect to my colleagues, I never liked the name ‘Warp Speed,’” Fauci said. “It has a connotation of almost reckless speed, and it’s not. It’s really the advances of platform technology that have allowed us to do in a matter of months that normally takes us years to do. .....The Chinese published the sequence of SARS-CoV-2 in a public database on January 10,” he explained. “I got my team together on the 11th (of January) and said, ‘We’ve got to partner with Moderna and put this in an mRNA platform.’ By the 15th, we started doing it. Sixty-five days later, we were in a phase 1 trial. And 7 months later, we’re in a phase 3 trial. That process would normally take a few years, but we didn’t compromise anything.”

At 12:21 PM, Blogger lukeness said...

You say that the death rate from mumps was about 1 in 10,000 and they estimated death rate of Covid is 2 in 1,000. 2 in 1,000 would be 20 in 10,000, which is 20 times the mumps death rate, not four times.

At 1:50 PM, Blogger Gaius Publius said...

Thanks, Lukeness. My bad. Will fix. Doing math in my head isn't always the best idea.

Anon, you may be right about the Moderna candidate, but I need to do more checking. Thanks for the heads up.


At 4:39 PM, Anonymous Anonymous said...

China, Russia and MAYBE the us might choose to do what the AEC did experimenting on radiation effects -- recruit hapless minorities and/or prisoners.

and the death rate among the elderly and co-morbid is, what, 10X... 100X the average?

I'm pleased that my grandkids might be ok. but I'm very uneasy about my wife, me and all our siblings.

not that anyone gives a crap about people older than 60.

At 8:09 PM, Anonymous Anonymous said...

how can they know what the death rate in covid cases is when they have no clue how many cases there are?

OR, to put it another way... just how many people have contracted covid since December? You only know how many you tested that came back +. You didn't test everyone. If you had, the number of cases might be 20 million or 200 million.

They know how many deaths. But if you know the numerator but have no earthly idea what the denominator is, you DO NOT KNOW what the ratio is.

At 9:19 PM, Anonymous Anonymous said...

When? Not until one of Trump's buddies has the monopoly on its distribution in the USA - and Trumpty-Dumpy gets a piece of the action as a "campaign contribution".

Ain't corrupt capitalism grand?


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