News about vaccine performance and vaccine rollouts has provided an embarrassment of riches lately, plenty to fill a blog post. I couldn’t resist a brief detour on variants, though, and a coda of prize headlines.
Two ticklish issues
Do vaccines prevent infection? The main aim of COVID-19 vaccines is to keep people from getting sick. But it would be nice if they also protected against getting infected, since asymptomatic people with SARS-CoV-2 living in their noses might be able to transmit the virus to others.
- Moderna’s vaccine does prevent infection. Their Phase 3 trial called for researchers to swab volunteers’ noses the day they returned for their second dose, and it found 15/14,550 vaccine recipients and 39/14,598 placebo recipients who felt fine but tested positive. That calculates as an efficacy of 62% against asymptomatic infection, though with so few cases we can’t be totally certain. Overall the Moderna vaccine reduced infection, with or without symptoms, by 89.6%.
- AstraZeneca’s doesn’t. It was the only manufacturer to get weekly nasal swabs on some Phase 3 volunteers throughout the trial, but the vaccine turned out to be completely ineffective in preventing asymptomatic infection (41/2692 cases in vaccine recipients, 42/2751 in the control group). The vaccine’s overall reduction in infection, with or without symptoms, was 54.1%.
- Pfizer’s might. None of their studies directly addressed the issue, but the company promised in its Phase 1-2 report that it would eventually do so indirectly, by using a blood test (for SARS-CoV-2 N-binding antibodies) that can detect asymptomatic infection.
- Sputnik V might. We’ll definitely find out eventually because Gamaleya, like Moderna, reswabbed people on the day of their booster shot, though they haven’t released those results yet.
- Novavax, Johnson & Johnson, and the Chinese: no comment.
Should COVID-19 survivors be vaccinated? Logically, people who have tested positive for SARS-CoV-2 should stay at the end of the vaccine line, at least for the 5 or 6 months of immunity afforded by natural infection. Additional light has now been shed by a new study from Moderna which found that people with pre-existing SARS-CoV-2 antibodies all had a humongous antibody boost days after a single dose of vaccine, and suffered particularly severe side effects. So if people who’ve ever tested positive are to be vaccinated at all in the short-medium run, which is questionable, they should definitely receive only one dose rather than two.
Johnson & Johnson: The biggest newsflash in this cycle involved Johnson & Johnson’s long-awaited interim Phase 3 results among 40,000-odd volunteers. But the mountain seemed to have given birth to a mouse, with vaccine efficacy of only 66%, far lower than either of the RNA vaccines. Efficacy was better in the US (72%), against the original SARS-CoV-2 virus, lower in South Africa (57%). Positive aspects: side effects were mild, there were no anaphylactic reactions, the vaccine only needs a single shot, and it will keep for 3 months in the fridge. The company is testing a two-dose regime, hoping for better results, but they’ve applied for emergency authorization from the US Food and Drug Administration anyway. Application to the European Medicines Authority should follow swiftly, with doses (already bought and paid for) reaching the EU as early as April 1st.
I and others have a niggling doubt about the Johnson & Johnson Phase 3 results, arising from what the company counted as a case of disease: not “any” COVID-19, like its competitors, but only “moderate-to-severe” COVID-19. On the bad end the vaccine worked great, preventing 100% of hospitalizations and deaths, and 85% of severe cases. We would also like to prevent “mild” COVID-19, because it can be debilitating and lead to long-term residual symptoms. But an even greater reason for concern is that Johnson & Johnson’s tougher endpoint may, perhaps paradoxically, make the vaccine look better than it actually is. Sinovac’s candidate vaccine, for example, had an efficacy rate of 78% against moderate-severe cases but only 50% when mild cases were included. I hope that when Johnson & Johnson publishes its data we will be given the information we need to compare efficacy with other vaccines, apples to apples.
Both Anthony Fauci and distinguished infectivologist Dr. Paul Sax see the glass half full, pointing out that the perfect should not be the enemy of the good and that unlike Moderna and Pfizer’s vaccines, this one was handicapped by having to wrestle with the difficult South African variant.
Novavax: The second biggest vaccine news is the interim results from this US vaccine’s Phase 3 trial in the UK: 89% effective overall among 62 cases of COVID-19. Like Johnson & Johnson’s the Novavax vaccine was much less effective in South Africa, 49% in the population as a whole, 60% when looking only at HIV-negative volunteers. Though it works splendidly against the strains dominant in Europe and the United States, this vaccine may not arrive in time to relieve Europe’s dosage drought. Both the US and the UK long ago reserved many millions of doses, but a contract with the EU that’s been in the works for months, is still not finalized. Damn.
Sputnik V: Back in November, when the Russians’ Phase 3 trial reached 78 COVID-19 cases, Gamelaya said their vaccine worked. Those preliminary results have now been properly published, reiterating an overall efficacy of 91.4% against “any” COVID-19 and 100% against “moderate or severe” disease, with no serious side effects. Efficacy did not vary by age, though few subjects were over 60 and almost none over 70. The one oddity I see in the report is that researchers excluded 39% of potential volunteers for preexisting conditions (Pfizer excluded only 3%). Otherwise the trial looks perfect. But . . . the research game depends on trust, and only the researchers themselves can know what really went on. Am I crazy for nourishing lingering doubts about the paper’s veracity based solely on the fact that this vaccine is the official product of a regime infamous for lying about everything from the doping of athletes to interfering in American elections to murdering its political enemies?
Some experts expressed concern about possible data fabrication when earlier Sputnik V data were published last September, pointing out what they called “strange data patterns”: “on the ground of simple probabilistic evaluations the fact of observing so many data points preserved among different experiments is highly unlikely.” (The most famous case of data fabrication in history, Sir Cyril Burt’s “proof” that intelligence was an inherited trait, was unmasked because of a similar defect.) The perfection of the new results could merely reflect progress in data fudging. In my humble opinion it would not be unreasonable for Western regulators to hold off on approving this vaccine until they see a couple of months of real-world experience in the countries where it has already been authorized: Belarus, Serbia, Argentina, Bolivia, Algeria, Palestine, Venezuela, Paraguay, Turkmenistan, Hungary, the UAE, Iran, Uruguay, the Republic of Guinea, Tunisia, and Armenia.
Sinovac: This Chinese contender, the 4th to release Phase 3 results last week, had to report cutting the rate of COVID-19 only by a disappointing 50%, despite not having to contend with the South African variant. As I’ve already mentioned, this vaccine did better at preventing severe disease.
AstraZeneca: As expected, the European Medicines Agency approved the Oxford vaccine. For now Germany won’t give it to anybody over 65 or Italy to anyone over 55. But new data are arriving soon that could change everything, because AstraZeneca’s Phase 3 trial in the USA expects its first results around the end of February. A quarter of its 30,000 volunteers are over 65, so we should soon know, at last, whether the vaccine is effective in the elderly.
A mystifying new preprint from AstraZeneca says it’s OK to leave 12 weeks between doses, as they are doing in the UK, because a single dose works just fine. Maybe even better than a double dose. And the longer a gap you leave between doses the better the vaccine works. Except if you wait more than 3 months, at which point the protection abruptly falls off the cliff from 76% to 32%. Huh? This paper is based on longer follow-up and thus more cases, but it’s still a methodological muddle. If volunteers received a single dose it was mostly because they chose to, and those who were elderly, male, or non-white generally chose to get 2 doses – creating a strong bias in favor of the one-dose regime that the authors did not even attempt to control for statistically. Most subjects were vaccinated single-blind, meaning the researchers knew who had gotten what, another potential source of bias. And, suspiciously, the 1-dose analyses were “post hoc,” i.e. not planned ahead of time. Overall efficacy in preventing symptomatic COVID-19 was similar to their interim results at 63.1% (74 cases in vaccine recipients, 197 in control groups), though maybe it was 82% after a 12-week rather than a 4-week booster dose. I’m not the only one to find this paper confusing and inconclusive.
Pfizer: The French pharmaceutical firm Sanofi, whose candidate vaccine flopped so badly it needs reconstructive surgery, is kindly inviting Pfizer to produce its own vaccines at Sanofi plants, which may make more Pfizer available for the EU – though unfortunately not before July. Meanwhile Israeli data say that COVID-19 hospitalizations plunge by 60% in the elderly just 3 weeks after the first Pfizer shot, even before full immunity is reached. This is great news, especially considering that hospitalizations reflect infections picked up a couple of weeks earlier. Pfizer hasn’t yet commented on the current CDC policy of allowing a 6-week gap between doses in a pinch, but I suspect they’ll be OK with it while continuing to nix longer gaps. Three weeks after a single jab vaccinees have neutralizing antibodies comparable to those in survivors of mild COVID-19. And in Phase 3 trials a single dose was highly protective starting 2 weeks after the shot. We don’t know how long that protection lasts, but it’s unlikely to fade away very fast, so lengthening the gap to 6 weeks should be fine.
Moderna: Their excellent Phase 3 trial results have now been published, but the company is not sitting on its laurels. Not only is Moderna busy developing a booster shot designed to protect specifically against the evasive South African variant, but it is also testing its vaccine in 12-17-year-olds, as far as I know the only vaccine maker to target adolescents. Good for them.
Curevac: This German candidate vaccine is of particular interest here in Europe because the EU has reserved a massive supply. All we know so far, from a preprint, is that it’s good at inducing antibodies, though at the cost of lots of side effects. Their Phase 3 trial only kicked off in December, so we’ll have no results for months.
Israel: Israel has now started distributing vaccines in the occupied territories, but instead of the top-line Pfizer vaccine they’re using Sputnik V for Palestinian health care workers, and plan to administer AstraZeneca when they get around to the general population.
United Kingdom: The British National Health Service continues to get high points for calling in enrollees systematically, in proper order, to get vaccinated, instead of making people waste hours at websites and call centers. At the same time it continues to accumulate demerits for favoring the AstraZeneca vaccine, especially in the elderly. But pushback is piling up against their one-dose vaccine policy, especially now knowing that AstraZeneca tends to stop working after 3 months (see above). One group of experts is calling the policy “a non-randomised, uncontrolled population experimental study without pilot data,” pilot data meaning a small preliminary study.
United States: Chaos still reigns. The New York Times calls the vaccination campaign a debacle it describes as rife with waste, confusion, and injustice, while a Facebook friend writes, “To get my 93 year old mother vaccinated in FL three people ran four computers for a total of 15 hours.” New York City has run out of vaccines, Governor Andrew Cuomo is feuding with all his public health officials, nobody can trace the 20 million doses scattered across the country, and black and brown Americans are getting (as usual) the short end of the stick in New York and elsewhere. But the United States is nonetheless way ahead of the EU, having administered 10 doses per 100 people instead of 2 or 3, thanks to a 3-week head start plus privileged access to doses being churned out by Pfizer and Moderna factories on American soil.
South Africa: Poor South Africa. Before the troublesome B.1.153 variant appeared on the scene, it unfortunately put its bets on the AstraZeneca vaccine, which is utterly useless against the local strain, and Johnson & Johnson, which has only limited efficacy. They’ve now wisely cancelled their orders for AstraZeneca, and are trying to get their hands on more Pfizer.
|Vaccination by appointment in Rome on February 8th|
Italy: According to an optimistically updated vaccine schedule all Italians over age 70 and all teachers, policemen, and prison personnel and inmates under 55 could be vaccinated by mid-May, the former with Pfizer or Moderna and the latter with AstraZeneca. But teachers and police are already putting up resistance against getting a second-tier vaccine.
For 3 weeks now Italy, with the rest of the EU, has been forced by the shortfall in Pfizer’s deliveries to use almost all its fresh vaccine doses as boosters. But at noon on February 1st Rome’s Lazio region finally dared to roll out a dedicated website and call center for over-80’s to arrange vaccine appointments. Both crashed instantly. At 10.30 PM I finally succeeded in scoring a February 22nd appointment for my 82-year-old husband. People who waited until the morning were given appointments in April. Miraculously, shots started getting into arms on February 8th, as scheduled.
Some Europeans are accusing Pfizer of giving the EU’s vaccine doses to the UK because the UK pays more. But Pfizer actually cut back its supplies to the UK as well as to the EU, and the EU’s small discount on the price is amply justified by vaccine development funding that was considered “down-payment on the vaccines.”
|Page from AstraZeneca-EU contract as publicly released|
War of the Roses: After Brexit, the ex-couple is scrapping over the kids. The UK announces it will cut the promised supplies of AstraZeneca to the European Union by 60%. The EU threatens to hold back Pfizer doses manufactured in Belgium in retaliation. Much turns on arcane clauses in the relative contracts, but the upshot is that the EU is getting royally screwed. If Johnson & Johnson and Novavax both get approved fast, and both fulfill their contractual promises, Italy and the rest of the European Union will be on track to reach herd immunity – 80% of adults vaccinated – by the end of September. If not, not.
A mutable virus
|Mutant, by Johannes Holm|
Why now? It is very likely that bad behavior last summer, and the coronavirus population bomb it caused in the fall, is the underlying reason all these mutants have been popping up this winter.
B.1.1.7 (England): As the English variant spreads across the United States I still see no reason to think is more contagious or more virulent. A London friend writes: “I shop around for shops that look like they keep their doors open and require masks.” Masks in shops are an optional???!!! Fortunately the Moderna and Pfizer vaccines probably work fine against the B.1.1.7 variant, Novavax a little less so.
B.1.351 (South Africa): The South African variant, on the other hand, is scary. The Novavax and Johnson & Johnson vaccines are strikingly less effective in preventing infections with it, and AstraZeneca’s is utterly useless. Pfizer is confident its vaccine will work against the variant. Moderna’s elicits fewer neutralizing antibodies against it, but the company thinks there are still enough of them to be effective. They’re hedging their bets, though, working on a booster shot aimed specifically at B.1.351 – both AstraZeneca and Novavax are likewise already working on fixes to improve their vaccines’ performance. But vaccine resistance isn’t the only reason for concern about B.1.351. Previous infection with the original SARS-CoV-2 virus, especially mild cases, seems to barely protect at all against reinfectionwith the South African variant, and it is relatively resistant to treatment with convalescent plasma (and therefore, probably, to monoclonal antibody products).
P.1 (Brazil): I’m still not sure how much to worry about this one – is it more contagious? Is it escaping antibodies in plasma? Is it resistant to vaccines? Despite scare headlines we have as yet no real evidence. Certainly P.1 is becoming the dominant strain in the Amazon area of Brazil. But, as with B.1.1.7 in England, it may not be intrinsically more contagious.
Pick a headline, any headline!
|Administering a dose of vaccine on the road rather than let it expire|
- Africa News: “Vaccinations are dangerous. If the white man was able to come up with vaccinations, he should have found a vaccination for Aids by now”
- This elaborate, pseudo-scientific conspiracy theory (not espoused by the head of Pfizer research, incidentally) has been thoroughly debunked
- When a visitor asked Rabbi Chaim Kanievsky what people “should take upon themselves so this disease does not get to them and there are no problems,” the rabbi replied, “They should learn Talmud.” – New York Times
- Weird Russian disinformation campaign. Think it’s convinced anybody?
- And so have 200 of the National Guardsmen who fought at their sides on January 6th. So many Capitol Police are out sick or quarantined that they’re having to work 14-hour shifts.
- The Oklahoma governor stockpiled millions of dollars worth of hydroxychloroquine on the President’s word. Now he’s looking to unload it.
When the Italians decreed army escorts for all vaccine deliveries to prevent pilfering, everybody thought “only in Italy." Wrong!
- This stem cell therapy not only doesn’t work against COVID-19, it doesn’t even contain any stem cells. And the woman who’s hawking it is yet another Republican politician.
Finally! I thank you for this concise overview of the existing vaccines. The vaccine lottery is a frustrating game. I appreciate your candor.ReplyDelete
Thanks for the kind words. It's not been easy to make sense out of all the information that's coming our way.Delete
Excellent, incisive summary/overview! I have passed it on to a number or friends, including physicians.ReplyDelete
Thanks a million. I'm always particularly glad when I know colleagues are reading.Delete
cheers and gratitude for our Dottoressa for keeping us so well-informed. thankful for your comprehensive reporting.ReplyDelete
Thanks, we have had our 1st Moserna shot. Will get the second on March 4. When should we go back home to Emilia Romangna. Also stuck in Berkeley nowReplyDelete
I'd definitely wait until 2 weeks after the second shot before doing any travel.Delete