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This week brought data from another Operation Warp Speed-sponsored clinical trial to its analysis point: the ENSEMBLE Trial evaluating the Johnson & Johnson (J&J) Ad26 vaccine against COVID-19. This vaccine uses a different mechanism to replicate the coronavirus’s spike protein in our cells and teach our immune systems to recognize the virus. Unlike Pfizer and Moderna’s mRNA vaccines – which use a lipid particle encasing the RNA of the SARS-CoV-2 spike protein – the J&J genetic recipe for the spike protein is carried into cells by a genetically engineered type 26 adenovirus, which has the SARS-CoV-2 spike gene encoded into it. What happens next is similar to mRNA vaccines: the spike protein is made, and our immune cells take it up and initiate the process of inducing anti-SARS-CoV-2 antibodies and T cells.
The J&J vaccine has several different immunological characteristics than the mRNA vaccines, and SARS-CoV-2 antibody levels from a single dose are not nearly as high as those seen after two doses of either the Moderna or Pfizer vaccines. But the T-cell responses to the J&J vaccine – what we call cell-mediated immune responses – are higher, especially in those we call killer T cells, or the CD8+ cytotoxic T cells, which seek out and destroy cells that are infected with the virus.
Another important difference in the J&J vaccine trials is that they were designed through an international lens: J&J is a global company with high production capabilities, which eases the burden of distribution. The J&J vaccine doesn’t have the cold-chain requirements of the two mRNA vaccines, and it’s quite stable at refrigerator temperatures (4 degrees Celsius) for extended periods of time. J&J’s Ad26 vaccine platform has also been used in Africa for preventing Ebola infections, in which the Ebola surface protein is placed into the Ad26 vector. Of note, the Ebola vaccine has been approved by the World Health Organization for preventing Ebola virus infections and has been widely administered to women of child-bearing age, pregnant women, and children. The Ad26 platform is also under investigation in elderly adults for RSV (respiratory syncytial virus) infections and in Africa and South America in preventive HIV vaccine candidates.
The J&J clinical trial was conducted in the United States, Mexico, South America (Argentina, Brazil, Chile, Columbia, Peru), and South Africa. The trial enrolled approximately 44,000 persons, of whom 19,302 were in the U.S.; 479 in Mexico; 17,426 in South America; and 6,576 in South Africa.
The initial analysis from the J&J trial data provided an extensive look at the vaccine’s effects, as more than 400 cases of COVID-19 occurred in study participants. This large data set allowed for a good look at the vaccine’s efficacy by country and region. Trial planning was done before the new variants were identified. Hence, it was fortuitous that within two months of identifying variants of concern, we “caught” the wave of the introduction of these variants in Brazil and South Africa. Thus, we now have real-world data on vaccine efficacy against the B.1.351 variant, which was first identified in South Africa and has multiple mutations that may permit immune escape, using a COVID-19 vaccine designed with an earlier variant as the immunizing strain. The point estimates for mild-to-moderate disease showed some difference by region – after one dose, the point estimate was 72% in the U.S.; 71.5% in Brazil; and 57.3% in South Africa. This was far better than the point estimate of the AstraZeneca vaccine to the variant (10.1%).
Fortunately, and importantly, for the J&J vaccine the efficacy against severe COVID-19 disease was high in all countries. In the United States, there was only 1 case of severe disease in the vaccine group, and 7 in placebo. For South Africa, it was 4 in the vaccine group, 22 in placebo; for Columbia, 1 in the vaccine group, 11 in placebo; and in Brazil, 1 in vaccine, 8 for placebo. So, in this one trial, the J&J one-dose vaccine offered anywhere from 82% to 90% protection against severe disease. The 6 deaths from COVID-19 in South Africa were all in the placebo group.
For a one-dose vaccine, these data are better than I initially expected. To illustrate this, I’ll include a link to materials that nicely demonstrate the J&J vaccine’s efficacy on moderate-to-severe disease in South Africa and on severe COVID-19 disease for the entire study.
The ENSEMBLE study outlines the complex nature of the human immune response to vaccination and the subsequent outcome. The antibody levels with the one-dose J&J vaccine are much lower than what we see with the mRNA vaccines and yet the J&J vaccine’s effectiveness against preventing severe disease – particularly against the B.1.351 South African variant – is quite similar. Why? What components of the immune response are central to this protection from severe disease? Antibodies? T cells? Both? These are issues we must decipher, and many of us expect that having good CD8+ T cells to the virus is an important function of the vaccine’s excellent prevention against severe disease. It is a nice scientific problem to have, how to go from 85% to 100% efficacy.
The question in front of us today is how do we use this vaccine in the U.S. and globally? It is, to date, the only vaccine for which we have good clinical data about both its effects in mild disease as well as severe disease with the South African variant, the cause for recent concern worldwide. The data from the two mRNA vaccines suggest that they are able to effectively handle the other emerging B.1.1.7 and California 20.C variants in the U.S. It is, however, the South African variant that we are most concerned about with respect to all the vaccine platforms in our current portfolio. As I mentioned earlier, the South African variant is one in which the two-dose AstraZeneca vaccine (chimpanzee adenovirus-based vector) showed no effectiveness in reducing even mild-to-moderate disease in young, healthy South Africans. The point prevalence was 10% with the two-dose AstraZeneca vaccine versus 59% in the one-dose J&J vaccine. These data, announced within a week, resulted in the South African government – which had purchased and had in-country more than a million doses of the AstraZeneca vaccine – to alter its rollout plan for use in health care workers and work with J&J instead to obtain its vaccine in an expanded access program. This dynamic interaction between clinical trial data and health care policy is what all these trials have been about.
The J&J vaccine is an extremely well-tolerated vaccine: fewer than 0.5% of enrollees had any severe (grade 3) side effects. It is easy to transport and distribute without strict cold-chain requirements and, as mentioned, we have extensive clinical experience with the Ad26 vaccine platform in pregnant women and children. Even though there is somewhat less efficacy with the J&J vaccine in preventing mild illness – such as a cough, fever, headache, or sore throat – than with the mRNA vaccines, the data from the J&J trial show that the severity of illness is significantly less after vaccination. I am gratified to see that both the FDA and CDC ACIP (Advisory Committee on Immunization Practices) advisors endorsed use of this vaccine for those 18 years of age and older. We hope and are pushing J&J to conduct its pediatric trials expeditiously so the advantages of a one-dose vaccine can be used to help get children immunized and back to school by the fall term.
Combating this outbreak requires achieving high vaccine coverage. Vaccination will also reduce the likelihood of more variants circulating. For all of these reasons, once we start to see 100 million doses of the J&J vaccine in circulation in the coming weeks and months, the data support widespread use of this vaccine in the U.S.