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.
 

Back To Normal? Oh, Sure

My best friends keep asking me when I think we'll be able to go traveling again. Are we going to France, Italy, Spain, Thailand, Morocco, India...? And when? My gut tells me it isn't going to be soon. I don't see 2021 as a year when things start heading back to normal.

On Wednesday Dr. Fauci sounded an optimistic note when he spoke to the Wall Street Journal CEO Council, telling the business chieftains that an effective vaccine and public-health measures could put the coronavirus pandemic "behind us" and that a return to a "reasonable form of normality" is possible by end of 2021. The Journal's Betsy McKay reported that he said "With a combination of a good vaccine together with good public health measures, we may be able to put this coronavirus outbreak behind us, the way we put the original SARS behind us." I suppose that was to calm Trump down after he flipped out about CDC head Robert Redfield's Senate testimony on Wednesday in which he said it would take a year before a COVID vaccine is generally available and that people should get used to wearing masks. Redfield responded to the senators "when" questions like this: "If you’re asking me when is it going to be generally available to the American public so we can begin to take advantage of vaccine to get back to our regular life, I think we’re probably looking at third-- late second quarter, third quarter 2021."

Trump blew his top and called him "confused" when he predicated that he thinks it will take a year before a coronavirus vaccine will be "generally available to the American public." Trump is telling voters "we’re going to have a vaccine in a matter of weeks." Redfield said there may be something available for first responders in November or December, which is not a message Trump wants out there. "I think he made a mistake with that statement," said Señor Trumpanzee. "When he said it, I believe he was confused. I’m just telling you we’re ready to go."

Nor did Trump enjoy Redfield telling that senators that he believes masks are "the most important, powerful public health tool we have" to fight the pandemic. "This face mask is more guaranteed to protect me against Covid than when I take a Covid vaccine." Noted epidemiologist Dr. Señor Trumpanzee called that "a mistake... Masks have problems too... A lot of people did not like the concept of mask initially, Dr Fauci didn’t like it initially." At his disastrous ABC News town hall on Tuesday night in Philly, Trump continued disparaging masks, telling a questioner that "a lot of people think the masks are not good," citing waiters as "a lot of people."

Trump also blew up when Biden noted that Trump isn't believable when he talks about a quick vaccine. The Washington Post's Sean Sullivan reported yesterday that most Americans distrust Trump on the question of a safe vaccine, "raising doubts about the president’s ability to put the health of Americans before politics... 'I trust vaccines. I trust scientists. But I don’t trust Donald Trump,' Biden said. 'And at this point, the American people can’t, either.' Biden also raised the possibility of President Trump pressuring agency officials to sign off on a vaccine that scientists are not yet confident in, to gain an electoral advantage."

Biden cast doubt not only on Trump but also on those around him. Asked whether he trusted the CDC and FDA, Biden said he did not trust “people like the fellow that just took a leave of absence.” He appeared to be referring to Michael Caputo, assistant secretary for public affairs at the Department of Health and Human Services, who urged Trump’s supporters to prepare for an armed insurrection and accused scientists in his agency of “sedition.”

As Biden addressed reporters, he attacked Trump’s handling of the pandemic and comments in an ABC town hall defending his administration’s response, despite widely documented problems with it. Biden urged Americans to ask themselves how it made them feel to hear Trump say he would not have done things differently.

Biden said people should not expect results just because the president is talking up the possibility of a vaccine. “Scientific breakthroughs don’t care about calendars any more than the virus does,” he said. He warned that politics should have no place in the production of a vaccine.

The Democrat’s position has become a point of contention in the campaign, with Trump accusing Biden and his running mate, Sen. Kamala D. Harris (D-CA), of spreading “anti-vaccine rhetoric.”

At a Wednesday news conference, Trump said Biden’s comments were “anti-vaccine” and “hurting the importance of what we’re doing.” He added, “I know that if they were in this position, they’d be saying how wonderful it is.”

Biden said he would have no problems endorsing a vaccine-- provided it met certain criteria. If the administration greenlights a vaccine, Biden said, “who will validate it was driven by science? What groups of scientists?”

He added that Americans must be confident “distribution will be safe and cost-free,” with a plan that is “without a hint of favoritism.”

...Biden also lambasted Trump for not aggressively encouraging mask-wearing and alleging that waiters do not like to wear them. The Democrat defended his own calls for a national mask mandate, saying he would seek to implement one by working with governors but was not completely sure yet what legal authorities he would have to deploy such a rule. (He said his advisers think they can create a mandate.)

It's worth remembering that just half of American bother using the annual influenza vaccine, even when it is given away free in supermarket pharmacies and when doctors tell their patients to get it. I suspect an awful lot of Americans are going to be far warier of any vaccine rushed onto the market to coincide with Trump's reelection efforts.

So... going back to my original question about renting a villa in Tuscany, a riad in Marrakech or a hut on Koh Pi Pi, The Atlantic's Joe Pinsker speculated yesterday that There Won’t Be a Clear End to the Pandemic and that "the collective sense of closure we’re all longing for may never arrive. Instead, brace for a slow fade into a new normal."

He wrote that, like our travel plans, "The pandemic has rendered many activities unsafe, but thankfully it can’t stop us from fantasizing about them. A common balm that people reach for is the sentence construction 'When this is over, I’m going to ____.' It seems to help, if only in a fleeting way, for them to imagine all of the vacations they’ll go on, all of the concerts they’ll attend, and all of the hugs they’ll give, as soon as they’re able to. Unfortunately, the sublime post-pandemic period that so many are longing for will likely not arrive all at once, like a clock striking midnight on New Year’s Eve. If and when the pandemic is over someday-- in the sense that it’s safe to resume normal life, or something like it-- pinpointing its conclusion may never be possible. Internalizing that, and mentally bracing for a slow fade into the new normal, might lead to less angst. Whatever the end of the pandemic might look like, the United States is nowhere close to it at the moment; week after week, hundreds of thousands of Americans continue to test positive for COVID-19, and several thousand die from it. But when the threat of the pandemic does eventually subside, the process will likely be gradual and incremental. 'I don’t think there’s going to be, all of a sudden, one day when we can all go make out with people at the grocery store,' Julia Marcus, an epidemiologist at Harvard Medical School, told me. 'Our concept of how the pandemic will end is just as oversimplified as the way we’ve approached everything else about it.' As a matter of epidemiology, there’s no clear-cut criterion that determines a pandemic to be over. 'You can’t sign a treaty with a virus, so we have to settle for a kind of cease-fire,' says Stephen Morse, an epidemiologist at Columbia University. One intuitive end point is full-on eradication-- meaning that the coronavirus no longer circulates in humans or animals-- but that outcome is quite unlikely, in part because of how easily the virus could continue to reach still-susceptible groups of people anywhere on Earth even well into the future."

The way that people process the end of the pandemic could have to do with how abruptly their life changes after it. One theory for how people mentally perceive transitions from one event to another is that they notice when their expectations of what will happen next start to get upended-- “like the disorientation you feel when a movie abruptly shifts to a new setting,” says Lance Rips, a psychology professor at Northwestern University. Under this framework, if someone undergoes a big life change during the final stages of the pandemic (say, moving or getting a new job after a bout of unemployment), they might be more likely to register a turning point. But if instead they merely start going out more, day by day, that might not yield the same discombobulation that can mark moments of transition.

Even if people crave a swift restoration of normalcy, many have come to terms with the fact that they won’t get it. “Wearing a mask is just like making sure you pocket your keys at this point,” says Athul Acharya, a 34-year-old lawyer in Portland, Oregon. The pandemic “has now lasted long enough that I, at least, don’t find myself waiting for the end. Looking forward to it? Yes. But anticipating it as a thing that will happen in the tangible future? Not so much.”

But a gradual fade-out-- one without clear indicators about the safety of resuming normal activities-- might be particularly distressing for some people. “Those with generalized anxiety disorder, in which a person experiences uncontrollable worry over a range of topics, could really be suffering,” Sandra Llera, a clinical-psychology professor at Towson University, wrote to me in an email. “If we don’t have a clear-cut ending, those with a tendency to worry”-- whether they have a diagnosable disorder or not-- “might experience a lot of stress about when we can begin to safely return to business as usual.”

This sort of uncertainty probably will, in a way, manifest society-wide during the pandemic’s final stages, as a politically polarized nation bickers about whether it’s really over or not. “It’ll be just as much of a mess as everything else that’s happened so far,” Marcus, the Harvard epidemiologist, said.

This dispute won't exactly be new: The country has been having a debate about whether the pandemic is over practically since it started. In late March, President Donald Trump said he’d “love to have the country opened up and just raring to go by Easter,” and in mid-June, Vice President Mike Pence wrote an op-ed asserting that “panic” about a second wave of infections was “overblown.” (Since the piece was published, some 75,000 Americans are estimated to have died from COVID-19.)

When the pandemic is actually petering out, public-health experts may have even more trouble conveying the precautions people should take when going about their day. “The particular challenge of a lack of a concrete end is that there is … a much more complicated calculus of what people should be doing in their behavior,” Rachael Piltch-Loeb, a fellow at the Harvard T. H. Chan School of Public Health, told me. In “a complicated, gray landscape,” she said, “there is more room for debate, error, and nuance in who should do what and when to protect themselves, their families, and their community.”