Moderna Vaccine Shows Reduced Activity Against South Africa B.1.351, Brazil (P.1), and California (B.1.427/B.1.429) Coronavirus Variants. However, it Remains Highly Active Against U.K. B.1.1.7 Variant

As vaccination rates go up and hospitalizations go down, there is finally reason for optimism in ending the covid-19 pandemic. But variants of SARS-CoV-2 could substantially impede our progress. Scientists are rushing to study whether antibodies generated by the currently authorized vaccines offer as much protection against emerging variants as they have been shown to provide against the original or "wild type" virus.

There are several ways to study this question. Three ways to study this are:

  1. Laboratory experiments of cells and viruses. 
  2. Animal studies
  3. Real-world data

Today, the New England Journal of Medicine released a paper by researchers at Moderna and their collaborators at the US National Institutes of Health. In it, scientists report data using the first approach; they measured how well antibodies taken from humans previously vaccinated with Moderna's mRNA-1273 shot (the one being rolled out to the public now) attach to and neutralize viral particles engineered to resemble the new coronavirus variants. 

Antibodies taken from patients who received the Moderna vaccine showed reduced ability to neutralize the coronavirus variants found in South Africa (B.1.351), Brazil (P.1), and in California (B.1.427/B.1.429). The good news is that the B.1.1.7 (UK variant) response was not affected. This is good because this variant has been shown to have a small but real increase in mortality. Of these, the South Africa variant evaded neutralization the most, with a decrease by more than a factor of 6. The reduction in neutralization against the Brazil and California variants was a factor of 2.3 and 3.5, respectively.

However, the neutralizations were still well above detectable levels. This means that it takes a higher quantity of vaccine-derived antibodies to get the same amount of neutralizing that occurs when the antibodies confront the "wild type" virus.

We don't yet know whether these new data will translate to any clinical impact among vaccinated persons. Many scientists believe that as long as antibody activity remains above a certain level, that the vaccines will still provide broad clinical protection against serious disease. The data today show that the Moderna vaccine is still well above that threshold. One possibility is that those who received the Moderna vaccine would still be protected against serious disease caused by the South Africa B.1.351 variant, but not against mild infection or the ability to spread the virus, especially to unvaccinated individuals. 

Yesterday, we learned that the Oxford/AstraZeneca vaccine does not protect against mild or moderate infections with the B.1.351 South Africa variant, though we do not know about whether that product still protects against more serious illness. On the hopeful side, the Johnson & Johnson vaccine, constructed similarly to the Oxford/AstraZeneca option, has indeed been shown to offer powerful protection against serious illness from the South Africa variant.

In the meantime, we await real-world data on hospitalizations and other markers of serious covid-19 in areas where the new variants are dominant. That will tell us, more than anything, just how the increasingly vaccinated population at large is responding to these new versions of SARS-CoV-2. Finally, scientists are likely to study what happens to non-human primates who are vaccinated and then exposed to a novel variant. So far, data on these experiments, assuming they exist, have not been made public. In an email to Brief19, Darin Edwards, the Director for Infectious Diseases at Moderna said, "I can't comment specifically on the non-clinical research efforts that we are performing in the variant space, but I will say we are trying to be as comprehensive as possible, as we were in the original evaluation of mRNA-1273.

Competing companies like Pfizer/BioNtech, Johnson & Johnson, and others are also likely to be addressing these concerns using a combination of the various approaches described above. If and when such data become available, they would add important information about what we can expect in the coming weeks and months. Any findings could determine the character of the next phase of the covid-19 pandemic.


Oxford/AstraZeneca Fails to Prevent Mild to Moderate Covid-19 From B.1.351 (“South Africa”) Variant

The rise of variants of SARS-CoV with alterations at the key spike protein, notably the “South Africa” variant (B.1.351), has posed potential challenges to the covid-19 vaccines. Many have expressed worry regarding the possibility of reduced efficacy of the currently available coronavirus vaccines, which were developed to combat the “wild type” virus that became pandemic one year ago. With numerous variants emerging since, scientists have begun to assess whether the game-changing vaccines being rolled out globally will still work against them.

In a randomized trial published in the New England Journal of Medicine today, researchers tested the Oxford/AstraZeneca viral vector vaccine in participants ages 18-65 years old in South Africa. Participants either received two “standard dose” vaccines or saline injections as placebo 28 days apart.

Among those that received the vaccine, 2.5 percent were diagnosed with mild-to-moderate covid-19 compared with 3.2 percent among those who received the placebo. Nearly all (93 percent) of those diagnosed with covid-19 were infected with the B.1.351 SARS-CoV-2 variant. Overall vaccine efficacy was quite low (at 22 percent) and even lower amongst those with confirmed cases of the B.1.351 variant (at 10.4 percent).

Yes, the results of this trial are disappointing. We would like to see good efficacy of the vaccine in protecting people from any degree of covid-19, asymptomatic or otherwise. However, we suspect that some headlines reporting this study to the mainstream media will present the findings as more doomsday than is owed. The results from this trial do not necessarily imply the Oxford/AstraZeneca vaccine is “useless” against this variant. While it is possible that this vaccine has reduced efficacy against more serious or critical covid-19, we simply do not know that from these data; there were no cases of severe covid-19 in either the placebo or vaccine group in the present trial. In fact, as the recent larger Johnson & Johnson trial in South Africa showed (which included many patients infected with the B.1.351 variant), at least one adenovirus vector vaccine constructed similarly to the Oxford/AstraZeneca vaccine has been shown to have good efficacy against the B.1.351 variant in achieving the overarching goal of reducing the number of people who get severely or critically with covid-19.

In sum, we now have data to suggest that adenovirus vaccines may not protect against mild and moderate covid-19 (Oxford/AstraZeneca) and data to suggest that this type of vaccine may yet still protect against serious and critical illness (Johnson and Johnson). If these data were to hold up, the pandemic would indeed eventually end even in places that only have access to these adenovirus options. We need to remember that the short-term goal of getting out of this pandemic is not eliminating mild and moderate disease; those cases we can live with. The way out of the pandemic is by eliminating the high number of hospitalizations and deaths; the high prevalence of such widespread and severe disease we can’t continue to abide.


Major NIH-Funded Trial of Convalescent Plasma in Covid-19 Outpatients Stopped Early Due to Futility

In another blow to convalescent plasma, the much-hyped proposed treatment for covid-19, the "Convalescent Plasma in Outpatient with COVID-19," or "C3PO" trial has stopped recruiting new patients and has been halted early, Brief19 has learned. 

The news was confirmed by W. Frank Peacock, MD, a researcher at Baylor College of Medicine in Houston who was involved in the C3PO study as a lead investigator at one of the 51 sites where patients were being enrolled.

During a planned interim review of the data, statisticians associated with the study deemed the efforts futile. What that means is that the board of experts monitoring the progress of the trial determined that even if researchers were to have continued to enroll more patients either to receive plasma or a placebo, there was no realistic chance that convalescent plasma therapy would come out a winner. The study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health (NIH), in a collaboration with researchers at Stanford, the University of Pittsburgh, the Medical University of South Carolina, and the SIREN network ("Strategies to Innovate EmeRgENcy Care Clinical Trials Network").

This news comes less than a week after a major "meta-analysis" (or "study of studies") was published in JAMA which found that when combining data from the best clinical trials studying convalescent plasma's effectiveness in treating covid-19 (mostly among hospitalized patients with more serious disease), no benefit was found with respect to saving lives, decreasing the percentage of patients who progressed to more serious or critical disease, and a number of other important indicators. 

Nevertheless, some had held out hope that less sick patients who did not yet require hospitalization might fare better and that convalescent plasma might still have a role to play. That is what the C3PO study was designed to study

The plan was to enroll 600 adult patients across 51 hospitals around the United States. Test subjects could enter the trial if they had confirmed SARS-CoV-2 infection and at least one symptom of covid-19, had one or more risk factors for severe covid-19, and did not need oxygen at the time of enrollment. Patients also had to have had symptoms for a maximum of 7 days at the time of enrollment into the trial. The idea was to find patients with relatively early, and milder illness who were at risk of getting worse, possibly progressing to requiring supplemental oxygen or more advanced care such as mechanical ventilation. The hope was the convalescent plasma might even keep some patients from becoming sick enough to necessitate hospitalization. The C3PO trial was primarily designed to determine whether or not convalescent plasma had a favorable effect on "disease progression," defined as "death or hospital admission or seeking emergency or urgent care within 15 days of randomization." No effect was found.

"With the termination of C3PO for futility, and this meta-analysis, we can't justify this treatment anymore," Dr. Peacock said in an email obtained by Brief19, who subsequently directly confirmed that the context for the comment was accurate. 

It is not unusual for a trial to be halted early for futility. But it is often seen as a fatal blow to that therapy. That said, it could be that limiting the enrollment to patients who were older and earlier in the course may have had some effect, which was that one glimmer of hope we've seen for plasma so far among many disappointing studies. We won't know until any data from the C3PO trial are published. 

But no matter how you slice it, this is a huge setback for convalescent plasma and more egg on the face of Dr. Stephen Hahn, former commissioner of the US Food and Drug Administration under Donald Trump. In August, Hahn heralded convalescent plasma as an important breakthrough in the treatment of covid-19. Even then it was clear that such a declaration was overstated and possibly even outright false. Hahn's now infamous statements at a White House press briefing reflected a view of the emerging literature that was remarkably amateurish, claiming that the therapy saved many lives, despite limited evidence to support the claim. Nevertheless, the FDA issued an emergency use authorization for convalescent plasma for treating covid-19 at that time, based on retrospective data, rather than actual clinical trials. Hahn's interpretation of the data at that time, which relied on subsets of subsets of patients who were never actually enrolled in clinical trials, was widely seen as yet another embarrassing example supporting claims that some of the FDA's decisions during the first year of the pandemic were politically influenced.

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