This article is reprinted from the Italian epidemiology journal Epidemiologia e Prevenzione, which commissioned and published it in both English and Italian
When the novel coronavirus, now known as SARS-CoV-2, clobbered first China then Italy in early 2020, most epidemiologists thought it could be contained easily, most virologists predicted effective treatments would arrive fast, and hardly anybody expected a vaccine before the end of 2021. They were all wrong. Non-pharmacological mitigation measures have failed, largely due to lack of political will; one magic bullet after another has proved ineffective; and vaccines arrived a full year earlier than predicted.
Prevention
Our most effective means of prevention are lockdowns, masks, distancing, ventilation, and vaccination, but we can also protect close contacts of infected individuals pharmacologically. Subcutaneous REGEN-COV (Regeneron’s combination of two monoclonal antibodies, casirivimab and imdevimab) lowers the rate of illness by a whopping 81.4%. This has been known since April and blessed by the US Food and Drug Administration at the end of July, but has not yet caught on, and the European Medicines Agency hasn’t spoken.
Outpatient therapy
A year and a half into the pandemic we’re not even close to finding a pill that can nip COVID-19 in the bud. Unfortunately scientists fixated early on hydroxychloroquine, largely due to French celebrity microbiologist Didier Raoult’s dreadful research (e.g. the abstract of this study neglects to mention that 4 of the 20 patients who received the drug, vs. none of 16 controls, wound up in the ICU or dead). Vast resources were squandered on hundreds of trials before it became clear that hydroxychloroquine is useless or worse.
Remdesivir, the only anti-SARS-CoV-2 antiviral in current use, requires intravenous infusion. A trial of a more convenient inhaled version in outpatients was completed in March but has not released any results.
For newly diagnosed patients at low-moderate risk of going downhill we have little to offer beyond antipyretics and home monitoring of oxygen saturation. The ancient gout remedy colchicine does cut hospitalization rates by 25% and the asthma drug, inhaled budesonide, by 18%. Fluvoxamine, an SSRI antidepressant, after very preliminary positive results last November, seems in a larger study to cut hospital recourse in high-risk patients by 30%.
Patients at high risk because of age or comorbidities should additionally be treated with one of 3 existing monoclonal antibody products aimed at the SARS-CoV-2 spike protein (others are under development). Hospitalizations fell by about 70% when high-risk outpatients were given Lilly’s combination of bamlanivimab and etesevimab or Regeneron’s REGEN-COV, and by about 84% with GSK-Vir’s sotrovimab, within days of diagnosis (this was all pre-Delta). These drugs are underused – only one in 4 eligible patients receives monoclonals in the US, and fewer than 7,000 patients have ever been treated in Italy. One reason is that they are usually given in a hospital setting by slow intravenous infusion – but the FDA (not the EMA) recently approved half-dose REGEN-COV as a convenient subcutaneous injection. We don’t yet know how well the antibodies work in breakthrough infections.
How about the variants? Alpha (B.1.1.7, first seen in England, and never a problem), Beta (B.1.531, South Africa), Gamma (P.1, Brazil), and Delta (B.1.617.2, India) are the main ones thus far. Lilly’s original monoclonal antibody, bamlanivimab, was useless against Beta, and its bamlanivimab/etesevimab combo was withdrawn for inefficacy against Gamma; REGEN-COV and sotrovimab do fine against both.
But Delta is the scariest. It’s 2-3 times as contagious as the Wuhan original, with a viral load up to 1,000-fold greater, and replication so efficient that infected people start spreading the virus within days. It may also cause more severe illness. Delta already causes almost all new cases in India, England, Israel, Italy, and the United States, and seems poised to take over the world. The Regeneron and Lilly products neutralize it fairly well in the testtube, and sotrovimab very well, though their real-world effectiveness remains unproven.
Still under study: Two oral antivirals, Pfizer’s PF-07321332, which began Phase 2-3 trials in July in combination with ritonavir, and masitinib, which is still in preclinical testing. The osteoporosis drug raloxifene; a trial has been completed but no results presented yet. Ivermectin has been more or less debunked in a Cochrane review, and some ongoing studies might stop now that a major article has been withdrawn for data fabrication.
Players around the world, including the “Medici Covid19” group in Italy and the “Front Line COVID-19 Critical Care Alliance” in the US as well as the governments of Brazil and India, promote multidrug cocktails to COVID-19 outpatients on the “Don’t just stand there, do something” principle. The most common components are known to be ineffective (hydroxychloroquine, zinc, azithromycin, vitamin D, ivermectin…). Others are valid, but only in selected hospitalized populations, notably systemic corticosteroids and anticoagulants. We know that COVID-19 patients taking steroids long-term for rheumatic diseases are at higher risk of hospitalization, and that they make inpatients not on oxygen more likely to die; the FDA recommends strongly against their use in outpatients. Anticoagulants are useless for outpatients, with the major trial stopped in June for futility.
Inpatient therapy
Monoclonal antibodies can help inpatients too, if they haven’t been sick long enough to develop their own antibodies. Non-pharmacological advances include proning, high-intensity nursing in the intensive care unit, attention to respirator settings, and strong preference for noninvasive oxygen delivery (C-PAP, high-flow nasal oxygen) over respirators.
Remdesivir: The only SARS-CoV-2 antiviral in clinical use, it was rushed to approval on the basis of a single studyfinding merely that it shortened hospitalization of COVID-19 pneumonia patients by a few days, with a nonsignificant trend toward fewer deaths. A Cochrane review as of April concluded remdesivir “probably has little or no effect on all‐cause mortality.” The CDC still mildly recommends its use, but the World Health Organization does not, and the death blow may be a July 2021 Norwegian add-on to the WHO Solidarity trial that found no effect on clinical measures or viral load.
Corticosteroids: Dexamethasone is the sole drug proven to save lives in COVID-19, decreasing mortality of patients on ventilators by 36%. Virtually all hospitalized patients on oxygen receive it.
Anticoagulation: Severe COVID-19 carries a high risk of thrombosis, so heparin derivatives are given preventively to most hospitalized patients, though patient selection, dose, and mortality benefit are uncertain.
Patients critically ill with COVID-19 are prone to “cytokine storm,” an excessive immune reaction that can lead to organ damage. The immunosuppressive tocilizumab (Actemra), an IL-6 antagonist used in rheumatoid arthritis, slightly lowers mortality and need for mechanical ventilation when added to steroids in selected patients. The oral JAK inhibitor baricitinib, which works similarly, has won emergency authorization in Europe and the US for patients who cannot be given steroids. Other immune modifiers under study include Saccovid and infliximab (by intravenous infusion), opaganib and the antimalarial artesunate (by mouth), and EXO-CD24 (by inhalation). WHO’s Solidarity trial is also studying the cancer drug imatinib, intended to counter pulmonary capillary leak in COVID-19 pneumonia.
“Long COVID”: Unfortunately there is thus far no treatment worth speaking of for the post-acute sequelae of acute COVID-19, which afflict as many as 77% of survivors after 6 months.
Numerous once-promising drugs have disappeared from view or failed to pan out. Oral: vitamin D, vitamin C, zinc, aspirin, fenofibrate, famotidine, raloxifene, enalapril, azithromycin, lactoferrin, multiple antivirals (lopinavir/ritonavir, darunavir, cobicistat, EIDD-2801), and a Russian mystery drug claimed to be “more than 99% effective.” Inhaled: nitric oxide and interferon-beta. Nasal sprays: dimeric lipopeptide, sticky polysaccharides, povidone-iodine, single-domain antispike llama antibodies, and REGEN-COV. Intravenous: placental stem cells, ruxolitinib, leronlimab, icatibant and, probably, convalescent plasma. Not to mention Trump’s bleach, Erdogan’s mulberry molasses, and John Magafuli’s artemisia (the President of Tanzania, killed by COVID-19 in March).
Vaccines
We’re doing vastly better on the vaccine front than on the treatment front, with a huge investment of effort and money, notably from Donald Trump’s Operation Warp Speed, producing and distributing multiple effective vaccines in record time. Already 68% of Italians, 60% of Americans, and 32% of all humans on the planet have had at least one dose of vaccine.
Most of the 138 candidate vaccines never made it into human arms, dozens, including apparently Italy’s Reithera, quit around Phase 2 (do we really need another viral vector vaccine, anyway?), and the German mRNA vaccine CureVac went through an entire randomized placebo-controlled Phase 3 trial before flaming out with only 48% efficacy. Israel is even testing a vaccine in a pill.
Approved by the World Health Organization
Pfizer-BioNTech: This US-German product injects messenger RNA (mRNA), which instructs our cells to fabricate SARS-CoV-2 spike protein, which in turn stimulates the immune system. The platform has already produced vaccines against diseases from rabies to cancer, but this COVID-19 vaccine was the first to reach the market. Its overall efficacy against illness and asymptomatic infection with the original Wuhan strain was an astonishing 95% in Phase 3 trials, and Phase 4 effectiveness in real-world vaccination campaigns has been at least as good.
Complete vaccination with Pfizer protects 95% against COVID-19 caused by the Alpha variant, 75% or more against Beta and probably Gamma. But Pfizer loses its punch against Delta, especially as time passes since vaccination. Reported effectiveness has varied wildly, from 88% in England to 79% in Scotland, 56% in Qatar and 42% in a Mayo Clinic Health System series.
The Israeli government supposedly estimated Pfizer’s protection against Delta infection at between 41% and 64%overall, falling to a scary 16% 6 months after vaccination. Protection against severe disease after 6 months was still 86%, but in people over 65 it was reportedly just 55%. When an actual manuscript (click on "preliminary report" in this article) was prepublished on August 25th, however, the numbers proved to be much less dire: protection of people over 60 vaccinated in January was still 55% against all infections during July’s Delta surge, and still 86% against severe COVID-19.
Vaccinated individuals with breakthrough Delta infections also have higher viral loads with Delta, and are therefore more contagious, than with previous viral strains.
Moderna: This all-American mRNA vaccine achieved a 94% overall efficacy against clinical COVID-19 in Phase 3 trials, and 100% against severe disease. Moderna behaves much like Pfizer except in one crucial way: it performs better against the Delta variant, with effectiveness of 86% in Qatar and 76% in the Mayo Clinic study.
The chief downside of both mRNA vaccines is the low temperatures needed for shipping and storage, an absurd -70º C.for Pfizer. Though Pfizer can now under some circumstances be shipped at -20º and stored in a refrigerator for a month, the cold chain is still something of a barrier, especially in the developing world. Another issue is cost, €18-€20 per dose now in Europe and about to go up.
Rare complications include anaphylaxis after 10 doses per million, possibly Bell’s palsy, and – of greatest concern – cardiac reactions, which may be more frequent with Moderna. Myocarditis usually affects young men after their second dose, and pericarditis older men (10 and 18 cases per million doses respectively). Most cases require brief hospitalization but almost none in the US have been fatal, and the risk to the heart from COVID-19 itself is far greater.
AstraZeneca: The “Oxford vaccine,” which uses a harmless adenovirus to deliver the spike protein to the immune system, was for months the most promising of all, and has the advantages of being cheap and easy to handle. But the research methodology behind its chief Phase 3 report was embarrassingly poor, the overall efficacy at standard doses in volunteers (all under age 60) was only 59%, and it is uniquely ineffective at preventing asymptomatic infection.
A later Phase 3 trial, performed properly in the US and Mexico, seems to have shown (all we have is press releases) that AstraZeneca does work reasonably well, at all ages, if the second dose is given on time after 4 weeks. Astonishingly, the investigators seem to have tried to fudge their results for this trial, despite knowing it would be scrutinized with a fine-tooth comb; they had to adjust the top-line efficacy result down from 79% to 76%.
I emphasize dose timing because a UK study claiming AstraZeneca worked better with 12 weeks between doses convinced many countries to institute that lengthy gap. Real-world research has shown, though, that one dose protected only 70% against severe COVID-19 in elderly Scots and even 2 doses reached only 80% in England, compared to 90-100% for the mRNA vaccines. Unfortunately European countries didn’t take the hint from the US trial, and have maintained long gaps between AstraZeneca doses. (The UK kept using the 12-week gap for Pfizer as well, even after data showed effectiveness to fall off.)
AstraZeneca works fairly well against the Alpha and Gamma variants but so miserably against Beta (10% efficacy) that South Africa cancelled its orders. Against Delta, a test-negative design study in Scotland estimated effectiveness at 60% overall.
Side effects have become a major issue. Severe blood clotting and bleeding (Vaccine-Induced Thrombotic Thrombocytopenia), especially in the brain, first came to light in Scandinavia in early March. UK officials steadfastly denied having seen any such complications until having to admit a month later that actually there had been 79 of them, 19 fatal – later updated to 242 and 49. and perhaps occurring, according to a study in Norway, as frequently as one in 26,000 doses. Most cases are in vaccinees under ago 50, so the EU, and eventually the UK, began giving AstraZeneca (and Johnson & Johnson) only to older people. Particularly wrong-headed because, as I just pointed out, AstraZeneca performs much less well in the elderly, at the 10-12-week dose gaps used in Europe.
Atypical cases of Guillain-Barré syndrome (sudden paralysis) have also been described following both viral vector vaccines.
AstraZeneca never seems to have provided the complete data promised 5 months ago to the Food and Drug Administration, but the United States, with its limitless supply of mRNA vaccines, can allow itself the luxury of giving AstraZeneca a pass.
Johnson & Johnson/Janssen: Similar to AstraZeneca in its viral vector technology but marketed as a convenient single dose, its overall efficacy peaks after 4 weeks at 66%. Johnson & Johnson shares AstraZeneca’s limited efficacy and its clotting problems, and probably its low effectiveness against the Delta variant. But it works much better against Beta(64% vs. 10%) and in preventing asymptomatic infection (74% vs. 2% [stet]).
SinoPharm and Sinovac: Both Chinese vaccines use attenuated virus. Sinopharm’s Phase 3 trial in young, healthy volunteers claimed 78% efficacy, and it is being used in more than 50 countries. The low efficacy of Sinovac’s CoronaVac, 51% in their pre-Gamma Brazilian Phase 3 trial, 42% in a test-negative case-control study against Gammain the elderly, and low antibody production against Delta, is feared to have contributed to surges in Brazil, Chile, Indonesia, Mexico, Thailand, and Turkey.
Phase 3 trials reported, no WHO approval yet
Novavax: A protein subunit vaccine, like the hepatitis B jab, that injects the spike protein itself. Results of Phase 3 trials in the UK (published) and North America (announced) both showed 90% efficacy. It’s only about 50% effective against Beta, though, and we don’t know yet about Gamma or Delta. On August 3rd the European Union ordered a supply, pending WHO and EMA approval.
Sputnik V: A viral vector vaccine, from Russia’s Gamelaya Institute. A well-published interim report of a Phase 3 trial claimed 91% efficacy, but data discrepancies in my opinion justify skepticism; Russia has denied access to raw data. The claim that Sputnik is the best vaccine against Delta is still just a claim. Sputnik also seems to have a quality control issue, with Brazil and Slovakia having to turn back bad batches.
No detailed Phase 3 reports available
CanSino: A one-shot viral vector vaccine used in China, Pakistan, and Mexico, claimed to be 66% effective.
Covaxin: A killed coronavirus vaccine developed in India and already used in a dozen countries after claims of 78% efficacy.
Abdala: Cuba claims its home-grown 3-shot protein subunit vaccine is 92.8% effective.
Vaccination issues
The Holy Grail: One advantage of mRNA vaccines is that they can be engineered to target a specific variant. But some scientists think it might be feasible, using any of several approaches, to create a universal mRNA vaccine effective against all strains of SARS-CoV-2 or maybe even of all coronaviruses present and future. Let’s hope!
Hesitancy: In the US vaccination has been highly politicized, with undervaccinated Trumpian areas now experiencing giant COVID-19 surges. Overflowing intensive care units in half a dozen states have hardly budged novax sentiment, which outside the US is falling everywhere. In Russia, whose skepticism rate of 47% leaves the US’s 28% in the dust, vaccine refusal long predates COVID-19. Germany has now surpassed France for the highest rate in Western Europe (19%), Spain has the lowest (9%), and Italy sits in the middle (16%). Vaccine refusers most often say that the vaccines are “experimental”; others fear side effects, think they’re invulnerable, or believe bizarre conspiracy theories. The most urgent and potentially most effective move to increase vaccination rates is therefore in the hands of the US Food and Drug Administration and the European Medicines Agency: give the vaccines full rather than emergency approval; the FDA has fortunately already done this for Pfizer. Green Passes, and vaccination mandates for medical workers and college students, are also proving persuasive. Access issues must be overcome by, for instance, facilitating home vaccination in Italy, where 8.6% of octogenarians are still not fully vaccinated, and ensuring that vaccinees do not lose wages in the US, where one in 4 workers have no paid sick leave.
Mix-n-match: Most European countries now give Pfizer or Moderna as the second dose to people who first received AstraZeneca, at least if they’re under 60. This is mainly to avoid clotting complications but there’s also reason to believe it will enhance efficacy, including against the Delta variant. It might also make sense at this point to offer a second vaccine dose some months after Johnson & Johnson, either of J&J itself or an mRNA product.
Boosters: SARS-CoV-2 antibody levels fall and breakthrough infections rise by 6 months after vaccination. And though COVID-19 survivors still have specialized anti-SARS-CoV-2 plasma cells in their bone marrow after a year, most experts think we will eventually all need mRNA boosters, ideally either universal or engineered to cover relevant variants. (Beware – the word “booster” is sometimes erroneously used for the 3rd dose the immunosuppressed need to jump-start their immune system.) Should we start now giving another dose to people who were vaccinated in early 2021? Israel is already offering the healthy elderly a third dose of Pfizer, though the Delta-blasting Moderna product might be preferable. The US and Germany will soon follow suit.
The more SARS-CoV-2 is circulating in the world, the more likely that terrible new variants will arise. That makes it selfishly as well as morally imperative to vaccinate poor countries, via the World Health Organization’s COVAX initiative or bilateral agreements. But I can’t fully agree with those who find it unethical for rich countries to give boosters when fewer than 5% of Africans have had even one dose. If the Israeli newspaper reports had been anywhere near right about the falloff in protection of our most vulnerable citizens, the elderly and sick who were first to be vaccinated, I would have definitely thought boosters for those groups appropriate and timely. Now that we know how exaggerated those falloff figures were, though, I’m tending to think the issue less urgent.
COVID-19 is a formidable enemy. With therapeutic options for hospitalized patients likely to remain limited for the foreseeable future, we need to put our energies into preventing severe disease in the context of a virus that is mutating faster than expected. That means we must rapidly upscale the use of monoclonal antibody therapy, overcome barriers to vaccination in rich countries, vaccinate poor ones with effective products, and invest in the development of universal vaccines.