SARS-CoV2: the outro
More vaccines, more variants, good news from Israel, bad news from New York, and some predictions
I’m hoping this will be my last COVID19 post for a long long time. I said at the beginning, JAM is about exploring the different corners of health and healthcare. Like all or many of you, I can’t wait to stop talking about this pandemic. Not saying I want to ignore it and start walking around maskless and hugging strangers. More that I’m already dreaming up titles for my next posts: “Coffee snobbery is healthy”, “What’s the deal with hangovers?”, “Sleep is medicine”, “The Healthcare Labor Force” and many more. Oh, and I have guest writers lined up as well! Stay tuned.
Okay, so we’ve talked about the first wave of vaccines, new SARS-CoV2 variants, “anti-vaxxers” and real world challenges in vaccinating a society. Since then, we’ve vaccinated over 40M people in the US; Johnson & Johnson says it has a single-dose vaccine that works well; we have published data on the Russian vaccine; Israel studied asymptomatic transmission in vaccinated people; the North Pole came to Texas, and Roaring Kitty, Robinhood, and a hedge fund showed us a gaping hole in American financial services regulations.
We have a single shot vaccine now
While Pfizer-BioNTech and Moderna grabbed all the vaccine headlines in 2020, JNJ quietly developed a single-dose adenovirus vector vaccine. This weekend, the FDA issued an emergency use authorization (EUA) for JNJ-78436735., based off data available to the rest of us via a recent JNJ press release describing the high-level efficacy and safety results. (I’m sure we’ll see the official peer-reviewed publication soon).
So how’d JNJ do? In general, it did well, but maybe not as well as the mRNA vaccines already out there. As with Pfizer and Moderna, the primary goal was to show that their vaccine kept people out of hospitals and ICUs, not that it prevented transmission (though, of course, that should be an expected secondary benefit of vaccination!). According to JNJ, their vaccine was “66% effective overall in preventing moderate to severe COVID-19, 28 days after vaccination”. That number goes up a bit after 28 days, and is quoted as being as high as 85%. This isn’t as inspiring as the ~95% protection seen with Pfizer and Moderna. But it’s a lot better than nothing!
A very important thing to consider is that more than 50% of trial participants were in Argentina, Brazil, Chile, Colombia, Mexico, Peru, and South Africa. This is important because, almost undoubtedly, many of these people - especially the South Africans - were at high risk of catching the new SARS-CoV2 variants we keep hearing about. (Because the Pfizer and Moderna trials studied patients earlier than JNJ, it’s unlikely those vaccines were exposed as much to the variants in the news today). When JNJ broke down the reduction in moderate-severe COVID19 (1-month after vaccination) by region, they saw a 72% decrease in the United States, 66% in Latin America and 57% in South Africa. As the South African variant spreads everywhere, we might see the real-world efficacy of the vaccine reach 57% across the board. Not as promising as the 66% advertised in the press release…but still better than nothing.
And did I mention that it doesn’t need a special deep freezer?
Sputnik V
"A vaccine against coronavirus has been registered for the first time in the world this morning… I know that it works quite effectively, it forms a stable immunity." That was Vladimir Putin declaring victory back in August. Almost 6 months later, we now have peer-reviewed published data on the real world effectiveness of Gam-COVID-Vac, a.k.a "Sputnik V, the Russian recombinant adenovirus (rAd)-based vaccine.
So, how’d it do? The Russians defined their goal as lowering the number of SARS-CoV2 positive cases after vaccination - which, taken at face value, is a higher bar to clear than keeping people out of the hospital! So given that goalpost, Sputnik V was 91% more effective than placebo (Lugonov et al, Lancet, Feb 2021). That’s pretty good - especially when you consider that Pfizer and Moderna’s results were in the 94-95% range . But let’s dive into a few things….
1) This trial was limited to Moscow. No one in South Africa, South America, Asia or even anywhere else in Russia was dosed with Sputnik V. So, ultimately ~60% of people who got the vaccine were white males.
2) When we try to do an apples-to-apples comparison with Moderna and Pfizer, we see that ZERO patients were reported to developed “moderate or severe cases” of COVID19. Not that the Moderna or Pfizer numbers were high, but they weren’t zero. I’m not entirely sure how to parse this result, but it’s quite remarkable…
3) Like Pfizer and Moderna, Sputnik V is a two-dose vaccine, with the second dose dose recommended 3 weeks after the first.
And not much to say about the side effects - pretty much the same as the other vaccines.
Adenovirus vaccines
Just a few words on vaccine “vectors” (e.g. the delivery vehicle that brings the SARS-CoV2 package into the human body). JNJ, Sputnik V, and others (including AstraZeneca) use adenoviruses; Pfizer and Moderna use mRNA (and Inovio, DNA). None of these technologies is “new”. They’ve all been studied and used for decades - just not at the scale we’re seeing in this pandemic!
Adenoviruses are everywhere in the world, and we catch them all the time. Sometimes they give us a day or two of diarrhea or a few days of pink-eye. Other times, if we’re older, we might get a more pesky pneumonia. It’s fair to say that by the time you’re an adult, your body has already been exposed to an adenovirus. This might explain why the JNJ vaccine appears to be a bit less effective than the mRNA vaccines. If you’ve already been exposed to an adenovirus in the past, your body might see the JNJ adenovirus vector SARS-CoV2 vaccine and say “oh, another adenovirus? Nothing to see here” and not ramp up an immune response to the level you’d like to see.
So why does Sputnik V - also an adenovirus vaccine - appear to do better than JNJ? One reason might be that JNJ uses only one adenovirus vector (Ad26) while Sputnik V uses two (Ad26 and Ad5). Another reason might be that two doses are better than one. And another reason might be that JNJ put itself against the toughest trial yet. While Sputnik V was limited to a very small part of a single country, JNJ vaccinated people across Africa, South America, and the US! In fact, JNJ vaccinated a more diverse mix of people than Pfizer and Moderna too.
Asymptomatic transmission after vaccination
A recent study by Dagan et al reports on Israel’s vaccination program. While they report fewer asymptomatic spread after vaccination, they also point out that "In the absence of systematic periodic testing of SARS-CoV-2 among asymptomatic people in Israel, documented asymptomatic infections do not account for all asymptomatic infections, and likely cannot capture vaccine effectiveness for this outcome.” In other words, if you’re not routinely testing everyone regularly, you’re probably going to under-estimate asymptomatic spread.
B.1.351 and B.1.526
I mentioned in an earlier JAM post that viruses always mutating. Variants are inevitable. Today, with SARS-CoV2, three variants in particular are in the headlines: “UK variant”, “South African variant (B.1.351)”, and “New York variant (B.1.526)”? The UK and South African variants are on every continent now, and my guess is the New York variant is clearing customs everywhere too. Annavajhala et al at Columbia University Medical Center describe B.1.526 in detail here.
In 2021, with millions of people already infected and recovered, and vaccines being distributed and dosed as fast as possible, I think the most important question on variants is: can immunity to one variant protect against another? And to what extent?
Lots of interesting stuff in the Annavajhala paper, but the most relevant finding to me is: “the neutralizing activity of REGN10987 against E484K pseudovirus is unaltered, but the activities of REGN10933, CB6, and LY-CoV555 are either impaired or abolished. Likewise, neutralizing activities of convalescent plasma or vaccinee sera are lower by 7.7-fold or 3.4-fold, respectively, against the E484K variant.” In other words: antibodies from previously infected people, and 3 out of 4 man-made antibodies against the original strain of SARS-CoV2 work less well against the New York variant.
Hot Takes
Of the vaccines in use today, Moderna and Pfizer appear to be at the top. Between JNJ, Sputnik V, and AstraZeneca, it’s a little less clear. By the published numbers, Sputnik V is the best of the 3 adenovector vaccines. But there is a huge asterisk there. Given the very limited population they tested, it’s hard to say how it’ll do against variants and in a more diverse society in general. Which is why I’m both a bit concerned and curious about many South American and African countries lining up for Sputnik V shots. I have to believe that this came down to basic supply and demand issues; Pfizer and Moderna preferentially sold into the more lucrative American and European markets (and a Russian vaccine was probably never going to find a buyer in the US or western Europe. Realizing this, the Russians saw the opportunity to sell into hungry and underserved South American and African markets.
For those who want to boil it down to “Abhi, which vaccine would you choose?”, let me first say that to even have a choice of vaccine is a HUGE privilege. But if you find yourself in the US of A, and in a position to choose, and can make time for 2 vaccinations, I would go with Pfizer-BioNTech… And if that’s not an option, then Moderna, followed by JNJ. That said, let me offer another scenario: you’re a reasonably healthy 36-year old male at the “vaccine store” and you and an elderly man are in the SARS-CoV2 aisle of the store, standing in front of the last two boxes of vaccine - one Pfizer, the other JNJ. You should hand the Pfizer box to the lady and take the JNJ for yourself. Why? Because she, on average, is at greater risk of ending up in the hospital than you are.
Asymptomatic transmission is real and probably underestimated. BUT, it’s going to be less common than symptomatic transmission for the simple reason that if you’re vaccinated, your body will recognize and kill SARS-CoV2 faster than if you weren’t already exposed / vaccinated. BUT, there are caveats. 1) I don’t know what these new variants mean for asymptomatic spread. Intuitively, it sounds like if antibodies from previously vaccinated or infected people can’t neutralize the New York variant very well, that could prolong the asymptomatic transmission window - or, perhaps, it might just cause symptoms and we’ll know we’re at risk of transmitting to others. 2) I think one thing we haven’t considered is the role of immunocompromised people in the pandemic. Anecdotally, whether due to medical advice or personal vigilance, people with autoimmune conditions, HIV, and cancer have been socially distancing more strictly than the general population. As these groups become exposed more and more (i.e. greater exposure to virus/variants via pandemic fatigue, increased social contact, or post-vaccination freedom), they will effectively become Petri dishes for the virus. We know that incubation times are longer in immunocompromised people. So while the virus might not put them in the hospital, it does use their body as a breeding ground - potentially for new variants.
With all these headlines on vaccine effectiveness and new variants, the number I continue to follow most closely is the hospitalization rate. Well, really, it’s a type of number, and it’s *local* hospitalization rates that I care about. In any case, this pandemic will become a series or collection of multiple epidemics, with different parts of our country and the world seeing different rates of infection and hospitalization. This will be driven by a combination of vaccination rates (i.e. ‘herd immunity’) and the characteristics of any new local variants that may develop over time. Regardless of how the pandemic evolves and/or fades away, hospitalization rates are what will affect the things we really care about: going out for an intimate dinner with friends, meeting a date for a drink at a dive bar, hugging a parent, buying cheap tickets on a crowded flight to the Caribbean, etc etc.
Public health surveillance will be a hot topic in 2021 going into 2022. And I wouldn’t be surprised if it’s something that’s heavily politicized going into the US midterm elections. Why? Because I think what surveillance will look like is everyday healthy or unhealthy people being asked by the government or a large biotech corporation to be swabbed or spit into a cup on semi-regular basis, and then running gene-sequencing tests on their spit or snot to identify and track the progress of more new variants - or new viruses entirely!