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Serious logistical issues have come up related to the fact that the COVID-19 vaccines that have received emergency use authorization (EUA) in the United States and the equivalent approval in other countries —the Pfizer/BioNTech and Moderna vaccines— require two doses in order to achieve the needed protection. This has generated debate and uncertainty over decisions on whether as many people as possible should receive the first shot without a guarantee that they’ll all receive the second shot at the correct time —three or four weeks after the first shot, depending on which vaccine is used, but recently the US CDC determined that the gap can be as long as six weeks for these two vaccines. Or, whether expansion of vaccination to an increasing number of people should hinge on the ability to deliver both doses according to schedule. The challenge has grown recently with a commitment by the administration of US President Joe Biden to get 100 million people vaccinated within his first 100 days in office. The uncertainty can be fairly nerve-racking, particularly if you are pregnant, what with all of the changes in your body and the planning for your delivery.
But maybe you also have heard recently that the COVID-19 vaccine that Johnson and Johnson has been testing in Phase 3 clinical trials will require just one dose, instead of two, like the vaccines from Pfizer/BioNTech, Moderna, and Astra-Zeneca/Oxford. That sounds attractive, as many people do not enjoy shots, nor the soreness that follows, plus it would simplify the logistics, if indeed the J&J vaccines could be administered one dose per person, thereby enabling more people to be vaccinated more quickly against SARS-CoV2 (the virus that causes COVID-19). The J&J vaccine has another logistical advantage that, like the AstraZeneca vaccine for COVID-19, the genetic material that triggers the immune response is carried in a virus that is more durable than the lipid particles that carry the genetic material of the mRNA vaccines (Pfizer/BionTech and Moderna). Thus, it can be stored at refrigerator temperatures rather than in deep freezers. The J&J data are encouraging, and yet they still need to be peer-reviewed and scientists both in and out of J&J have to look at more study participants, over a longer period, to see whether the single dose regimen pans out.
But let’s imagine that the data do indeed turn out to support a single dose regimen. In such a case, what is it about the workings of the different vaccines that makes one vaccine effective after only one shot and another effective, only after a second shot? As you may imagine, the answer is complicated, so we will need to simplify it, and there are many uncertainties. Each vaccine is given at a certain dosage because that dosage represents a balance —a Goldilocks zone of sorts— between immune effectiveness and adverse effects. Thus, in some cases, the vaccine may not provide enough protection after just one dose, because the amount that you can receive in the first dose is enough, only to prime to the immune system, yet not enough to produce the amount and type of immunity needed to keep you from getting sick in the event the you are exposed to SARS-CoV2.
Along with the dosage of the first shot, however, there is also the possibility that the particular characteristics of the tiny vehicle in which the genetic material of the vaccine is carried in the fluid that is injected into your arm may play a role in how the initial immune response plays out. In the case of Pfizer/BionTech and Moderna, the carrying vehicle is what researchers call a lipid nanoparticle. Such particles have very minimal effects on the immune system, which is good, because it means that you can get this type of vaccine over and over again. The job of these particles is merely to enclose the genetic material of the vaccine, which is messenger RNA (mRNA). On reaching the surface of a cell in your body, a nanoparticle becomes part of that cell’s cell membrane and in doing so it delivers the mRNA into the cell’s cytoplasm. There, the mRNA is read, or translated, into the spike protein, the same protein that the SARS-CoV2 virus has sticking out from its coat. But instead of making virus particles, your cells just make the spike protein and send it to the outside of the cell membrane, where it sits attached to one of two proteins.
One of these proteins, called MHC-I, is present on all of your cells that have nuclei, including muscle cells and since the vaccine is injected into the deltoid muscle on your arm researchers expect that much of the vaccine will produce spike protein attached to MHC-1 on muscle cells. The other MHC protein, called MHC-2, is present on the surface of only certain cells, known as antigen-presenting cells (APCs), consisting mostly of macrophages, dendritic cells, Langerhans cells, and B lymphocytes. While the presence of the spike protein attached to MHC-1 on muscle cells, or other cells with MHC-1, only can stimulate the production of antibodies, which come from a type of B lymphocyte, this is not really enough to create immunity against a new foreign agent, or antigen, in this case the spike protein. Rather, to get immunity going in a serious way, you need what is called a T-lymphocyte, or T cell response, which gets triggered significantly, when APCs present the antigen on their surfaces, attached to MHC-2.
According to Johnson and Johnson, not only is the J & J COVID-19 vaccine partly effective in producing an antibody response after the first dose, but there is a T cell response, even before a second dose is administered, whereas the two mRNA vaccines —Pfizer/BionTech and Moderna— produce a T cell response, apparently only after the second dose is given. There are different possible reasons for this, although it remains to be determined, which, if any, is the correct reason. On one hand, in contrast with the lipid nanoparticles that carry the mRNA vaccine genetic material, the genetic material of the J&J vaccine (as well as the AstraZeneca/Oxford vaccine), which is DNA, is carried in a kind of virus. Of course, the carrying virus is not SARS-CoV2; it’s a different virus, called an adenovirus. But the carrying virus itself, the adenovirus, has advantages over the lipid nanoparticles, one being that the virus, and thus the vaccine itself, can be stored for long periods at only refrigerator temperatures, whereas the mRNA vaccines require deep freezers. Also, the virus does cause an immune response and it could be that such a response is priming the immune system in a way that gets a T cell response to the spike protein on the surface of APCs after the first dose. On the other hand, it could be that, since the J&J genetic material is DNA, which ends up, not merely in the cytoplasm of body cells, but in the nucleus, where it lasts much longer than mRNA, this vaccine ultimately produces more spike protein on the first dose, in all cells that receive it, including APCs. This is extremely speculative, to be sure, but drives home, both the complexity of the vaccine technology and the beauty of the biological response that researchers are harnessing to protect humanity against this devastating disease.