Where We're Headed With Delta and To Boost or Not To Boost
What's on the mind of many is the Delta variant. How does Delta compare to prior variants and the original strain and where are we headed in the pandemic because of Delta?
Delta seems to be different compared to other variants. The Alpha variant already had high infectivity, but Delta is much more infectious than Alpha. That's one of the issues that we're facing. It's more infectious and it replicates better in the upper respiratory tract. We are also seeing more breakthrough infections and even transmission in vaccinated individuals. That's a problem.
If you look at different countries and regions worldwide and what it looks like right now in the United States, we might be at the peak of the Delta wave and cases might come down. In the UK, cases started to come down and then went back up. But in other countries, the Delta wave isn't actually that big and hopefully will be short, but currently unpredictable.
Immune Response: Vaccines vs Natural Infection
Antibodies and immunity can be a very confusing issue. What are we measuring? What does it tell us about immunity? What is the difference between the nature of antibodies from vaccine and from natural infection?
Binding antibodies are easy to measure and neutralizing antibodies neutralize the virus and are a correlate of protection for SARS-CoV-2.
There are also differences between immunity that is induced by natural infection and what is induced by vaccination. If you get a natural infection, you develop antibodies and those antibodies are also neutralizing, but the response is variable. Some people have very high antibody responses and some people have low ones (this was also seen with historic live viruses, such as the smallpox vaccine - as the inoculation dose could vary). In addition to that, with natural infection, you get these T-cell responses not just to the spike protein, but to the whole range of proteins that the virus has — and there are a lot of proteins that are encoded by SARS-CoV-2 — and you also get mucosal immunity because the virus replicates on mucosal surfaces.
This is in contrast to vaccination, where we basically get a response only against one spike protein, though with very high neutralizing antibody titers. And in healthy adults, the responses are usually the same — everybody has a high response, since the dose is controlled. But with the vaccine, you're lacking on the mucosal immune response and your T-cell response is only focused on the spike protein because that's what's in the vaccine. So there are differences, and this might lead to different types of protection.
It is currently recommended that if you had an infection, that you still get vaccinated because people who had an infection have variable titers. If you get vaccinated on top of natural infection, you bring these titers very high. Actually, people who were infected and then got vaccinated have a very broad and very high antibody response, even better than people who just got vaccinated. I often say that those who've had COVID are the safest people to be around.
The Truth About Antibody Tests
What a lot of us would like to know, is if there is a test that would show whether someone had prior COVID? Approximately 40 million Americans have had COVID infection, as confirmed by PCR or some other test, and probably another 90 million Americans were infected but didn't have a confirmatory test at the time. Is it possible to differentiate a natural immune response from a vaccine response by testing? FYI most of the current antibody tests are for IgG binding antibodies and not for neutralizing antibodies.
A lot of people who had gotten antibody tested after being vaccinated showed a negative antibody response. This would be the case if they had done a nucleocapsid protein antibody tests. Obviously these folks were upset that they didn't make a response. But it turned out that they were just measuring the wrong antibody response.
There are two targets for antibody tests out there, one for nucleocapsid proteins and one for the spike protein. You would only make antibodies against nucleocapsid proteins if you were infected with the virus or if you received one of those whole-inactivated virus vaccines that are used outside of the United States (which is what many traditional vaccines are), but this vaccine is rare to find here in the US. So if you have antibodies to a nucleocapsid protein, that suggests that you had an infection. If you have antibodies to the spike protein, it could be from an infection or from vaccination. If you haven't been vaccinated and you have spike antibodies, it's probably because you were infected. But antibodies against the nuclear protein vs spike protein let you differentiate because if you were vaccinated only and did not have an infection, you would have spike protein antibodies only. Labcorp now measures both antibodies to spike protein and to nucleocapsid proteins.
In terms of levels of antibodies, some antibody tests give you a yes-or-no response. That is okay to figure out if you had an infection or not, or if you made an immune response to the vaccine. But that's all it can tell you. Then there are antibody tests that are quantitative, that tell you what level of antibody you have now. It's correct that these antibody tests are not measuring neutralizing antibodies; they're measuring binding antibodies. But what we have seen in general is that there's a relatively good correlation between neutralizing and binding antibodies. In fact, studies coming out recently from Moderna have begun to establish a number that is connected to protection. There isn't a single number above which you know you're protected, and below it, you're not, it's usually a probability. Typically what is established with a correlation is a titer of antibody that reduces your chance of getting an infection or disease by 50%. Those values are starting to come out in scientific papers.
Should Prior COVID Be Counted as a Vaccine Dose?
Prior COVID doesn't get much respect. If you get a vaccine card, there's no entry for prior COVID. In many other countries, confirmed prior COVID is counted as one dose of vaccine in terms of your vaccine status.
There is evidence in which prior infection is is as good as what is seen with vaccine effectiveness against Delta with AstraZeneca, Moderna, and Pfizer-BioNTech vaccines, in the range of 70%-80% protection against reinfection with the Delta variant. So to assume that somebody who had an infection has no protection is wrong. Those people have substantial protection, though they have variability in their response. Some might get reinfected and are less protected than others, but they certainly have a degree of protection, at least a one-dose equivalence from a scientific perspective is what is being accepted in the scientific community.
The initial studies conducted in December 2020 and January-February 2021 showed that previous infection is about 80%-90% protective against reinfection, and protection against disease was even higher.
Is There A Time Cut-off of Immunity with Prior COVID?
There is a lot of talk about waning immunity from infection with COVID-19, and now we are hearing waning immunity about the vaccines. Waning immunity is a natural response to infection and antibody response after natural infection does stabilize over time, meaning it plateaus.
In current studies that are still ongoing, people who got infected and did not get vaccinated, are showing that their antibody titers are now pretty stable. As time goes on, it is likely that protection would still be there. It's not 100%, but there is certainly a good amount of resistance to infection over the long term.
To Boost or Not to Boost
There are a lot of things that you have to consider when you think about booster doses, such as waning immunity, and risk for disease. First of all, there is a difference between infection and disease. You see a lot of news reports out there that compare the efficacy of the vaccine against disease with the effectiveness against infection, and those are apples and oranges. You cannot really compare them.
There is a difference between infection and disease. You may have an infection or re-infection with COVID-19 and have no symptoms, therefore no disease. But when you have infection or re-infection with COVID-19 and symptoms, whether mild or severe, that is disease. The scientific community is interested mostly in preventing disease, not necessarily infection.
Now the efficacy data we do have, and Pfizer, for example, has data for 4-6 months, we do see a drop in efficacy of the vaccine at preventing disease. This makes sense because there is some waning of immunity initially in natural infection too. In addition to that, we have the delta variant circulating right now that seems to grow to higher titers and it's more infectious. The question is, when vaccine effectiveness falls to levels like 80% against disease (and scientists refer to disease, not infection}, is it time to give a booster shot or are we still good? Basically how do the levels against severe disease and hospitalization look?
Also, we need to look at the populations we want to give a boost to, such as those who are immunocompromised or older individuals who did not make a good immune response to the vaccine. In these cases, a booster dose may make sense.
But does it make sense for the general population to just, as a blanket policy, recommend a booster? You would need a lot of data to support that and we don't have that data at this time. It's true we do see some waning of vaccine effectiveness over time which is true of natural immunity as well, and we are seeing antibody titers stabilize. The question is where you end up, where does your antibody level stabilize at and fall no further? If you end up at the 85% effectiveness against disease, that's probably okay. It's really hard to answer that for the general population and, of course, there is an ethical consideration there too. We're now talking about giving booster doses potentially to people who don't need them, while a large proportion of the globe has no access to any vaccines. That's also something that we should take into account.
Comparing mRNA Vaccines
Most people don't question the difference between vaccines, whether one is better than the other. Most of us received the vaccine that was available to us at the time.
First there are differences with the formulation. The lipid nanoparticles are different and the dose of RNA that is delivered is different, though the genetic sequence is basically the same. The Moderna vaccine has 100 µg of RNA; the Pfizer vaccine has 30 µg. So there's that difference in dosage if you will.
There are also differences in spacing with Pfizer and Moderna: 3 weeks vs 4 weeks. Other countries that have seemed to do very well have used 8- to 12-week spacing of all the COVID-19 mRNA vaccines. Typically, we know that vaccines work better when you leave more time between the prime and the boost. Of course, between the prime and the boost you also have more vulnerability to become infected because your protection is not optimal yet. In a pandemic, you want to have a very small window. The UK had a different strategy. They had a very large window between the primary and the second dose, and that might in the end have produced a better immune response.
For example if you compare the UK with Israel — In the UK, the Delta wave is massive, but the deaths associated with the Delta wave are very low. They had very few deaths compared with the Alpha wave; it's night and day. In Israel, that doesn't seem to be the case. This brings up the difference in spacing between the first and the second dose of the vaccine, is longer spacing better? But this is a hypothesis that has not been confirmed.
Is one mRNA vaccine more effective at preventing disease than the other? Due to the difference in timing of roll out of the Pfizer vs Moderna vaccines and changes in infectivity of variants as time went on, waning immunity of prior infections and vaccines, scientists just don't have that data yet.
Mix or Match Vaccines?
There's a lot of interest in the mix and match of vaccines; the fancy medical word is "heterologous." The whole idea is that if you give a vaccine with the adenovirus vector first (like the J&J vaccine) and then give an mRNA vaccine, that seems to be the second best in terms of a potent immune response compared to after prior COVID and a vaccine, which so far shows the best immune response. But order matters, as it doesn't seem to work as well the other way around, if you were to give the mRNA vaccine first. But the mixing appears to work better than two mRNA vaccines or two adenoviruses vaccines.
Scientists do not understand the actual mechanism of this though it is something we have seen in the past. During influenza and HIV vaccine trials, scientists observed, even if they were not successful in the end, they were successful in inducing stronger immune responses when they used different vaccine platforms in combination, such as vaccinating first with a virus vector and then with a recombinant protein vaccine.
So it seems that all of these platforms stimulate the immune system slightly differently, and if you combine these stimuli, the immune system actually makes a better response. That could be a longer-lasting response, a stronger response, or in some cases, a broader response.
A Pan-Coronavirus Vaccine
So wouldn't we be better off having a Delta vaccine or a universal vaccine for SARS-CoV-2 virus, known as a pan-coronavirus vaccine?
If Delta keeps dominating, that might be a consideration at some point in time, which would be relatively easy for the mRNA vaccines. But since the current vaccines protect against the Delta variant, right now it doesn't look like it's necessary.