The New York Times morning briefing quoted a New England Journal of Medicine vaccine FAQ (https://www.nejm.org/covid-vaccine/faq): “If there is an example of a vaccine in widespread clinical use that has this selective effect — prevents disease but not infection — I can’t think of one!"
That doesn't match my understanding from what you've said here. Can you think of any examples of vaccines that prevent disease without providing sterilizing immunity? If not, what is it about SARS-CoV-2 that makes you think our priors from previous vaccines might not apply?
I find Dr. Sax's answer on this--and the fact that it appeared in the NEJM without being corrected--very puzzling, because it's wrong. Pretty much every virologist who has seen that claim has been scratching their heads about it because numerous vaccines in routine clinical use have disease-attenuating effects without providing sterilizing immunity. I've seen a couple of Twitter threads about this today, because of how incorrect it seems to be.
For example, the influenza virus vaccine *can* provide protection from infection, but it doesn't always. However, even if it does not provide protection from infection it is known to provide a spectrum of protection from disease, eliminating it entirely or lessening its severity.
The inactivated polio vaccine (IPV) is known to prevent conversion of polio infection from a gut infection to a neurological disease. It doesn't prevent infection by polio in the gut.
The herpes zoster vaccine also doesn't prevent infection, as I understand it, but generally this vaccine is used in people who are already infected in order to prevent symptomatic disease (shingles) in the case of virus reactivation.
If we go into the realm of bacteria, there are additional vaccines in widespread clinical use that prevent disease without preventing infection, but I'd rather stay in my lane of viruses since I've described enough examples already, all of them in widespread clinical use.
Another problem with this answer is that it doesn't actually matter whether the vaccine prevents infection or not, at least not for the purposes of answering this question. It seems like Dr. Sax is conflating infectivity with transmissibility, which isn't correct. Just because a virus can infect a host does not mean that that host can then spread the virus again. The issue being addressed by the question is whether the vaccinated host can spread the virus again, not whether they can be infected with it. It's true, though, that a vaccine which causes sterilizing immunity (prevention of infection entirely) will also prevent transmission, because the virus never infects and never replicates. What is less clear is whether, in the absence of sterilizing immunity, the virus can still be transmitted from the host.
The best example of this situation is with the IPV, where immunity is not sterilizing and people who have received the vaccine can very much play host to, and continue to transmit, the polio virus. It's a real thing and I'm surprised an infectious disease doc like Dr. Sax is unaware of it. Perhaps he is not aware of it because he largely practices in the US, where polio has been eradicated. This eradication is actually part of the reason that the US switched from administering oral polio vaccine to now using IPV; since the virus is no longer actively transmitting in the US, IPV is considered a safer option. The oral polio vaccine has a chance of reverting and causing polio in some patients.
We really just don't know the answer to this in the context of SARS-CoV-2. I believe it is likely that there is an effect on transmission in the context of these vaccines, but without data I am giving you a hypothesis, and I've had a lot of hypotheses in the past that have not borne out in the data.
Let's explore the hypothesis, though. First, we have to imagine two possible conditions. (1) The vaccine provides sterilizing immunity; in this situation, there is never an infection and so disease and transmission are bother prevented (2) The vaccine prevents the virus from causing disease by controlling the infection; sterilizing immunity is not achieved
(2) is a situation that could be caused by a number of different effects. It could be that disease is mostly mediated by an immune overreaction and when immune memory is present, that effect is reduced but the virus still replicates adequately to spread. We know that this situation is possible because we have evidence of people who are asymptomatic being able to transmit SARS-CoV-2 to others. So it's not beyond the realm of possibility that we have created more asymptomatic carriers with this vaccine. On the other hand, control of the disease may be achieved through an immune response that reduces the overall replication of the virus, and thus prevents transmission as well. This also seems fairly plausible.
As I've said in the past, I think it's also possible that the vaccine causes some kind of intermediate state--disease is no longer possible, and the capacity for transmission is reduced but not totally eliminated. I mention this possibility because it's important to realize that very few biological processes are binary. There is usually a continuum of possible states that exist between two potential extremes. This is one reason we need data on the ability of the vaccines to prevent transmission.
Back to the subject at hand: Due respect to Dr. Sax, I think he just gave a bad answer here. We all do that sometimes. He was asked about transmission and he answered about infection. Worse, he answered incorrectly about infection. I think that NEJM should retract the post. it's causing confusion and it doesn't contain accurate information.
There are at least two vaccines in development administered as nasal sprays (one from China, one developed by Lancaster University in England, in association with a the Biomedical Research Institute in Texas). Presumably nasal spray vaccine would induce an IgA response and be more likely to block infection, as opposed to "merely" disease.
In theory, yes, nasal spray vaccines ought to induce an IgA response. But of course, we need testing of each vaccine to demonstrate that this is the case. I'd love for that to happen and be successful. I'm sure that's underway.
Hey, John, have you written about antivirals? A diet of all vaccine essays is probably getting dull, and I find it disappointing that we still have no effective antiviral medications against SARS-CoV-2. (No, I don't think that remdesivir is actually doing anything.)
I wrote a couple of things about antivirals in the past, but I haven't in awhile. I'm not sure how I feel about remdesivir. I think its early clinical trial performance made sense in a systemic way but not on an individual patient basis.
I can write a little more about antivirals in coming days. Personally I do not think antivirals in a traditional sense are even half as useful as vaccines. Antivirals often don't perform the way we would hope--even eliminating 90% of the virus culture in a laboratory experiment often translates to very weak clinical benefits.
However, I do think some of the results with polyclonal antibody cocktails have been impressive. And the research involving steroid use has been very interesting as well. When a news story pops up on this I'll try to give it some coverage. Thanks for the suggestion.
I'm only aware of one disease where antivirals are really effective, namely AIDS/HIV infection. Not only are there effective treatments, there are not one, but two effective preventative meds. I'm sure you know orders of magnitude more than I do.
There are two viral diseases that come to mind for me. The important part here is that both are for chronic viral illnesses, which I think changes the dynamic of the situation.
You've mentioned one of the two, but I think it's worth noting that these antivirals for HIV are not curative. They vastly extend patient lifespan, but if discontinued the infection will once again take over. It is also possible for resistance to evolve, requiring a change in drug regimen.
The other is hepatitis C virus, which can actually be cured by antiviral agents. That was an amazing achievement that has really reduced the need for liver transplants around the world.
There are some other antiviral options that are somewhat effective against various infections but very little that compares to these two examples. Biologic rather than small molecule approaches have recently been pretty effective in a few virus-treatment situations, though. Regeneron, known for its COVID-19 antibody drug, also developed something similar for ebola virus that has really improved survival rates from that virus. I suspect that biologic approaches to antiviral treatment are going to be an area of expanded research in the future after these successes.
The New York Times morning briefing quoted a New England Journal of Medicine vaccine FAQ (https://www.nejm.org/covid-vaccine/faq): “If there is an example of a vaccine in widespread clinical use that has this selective effect — prevents disease but not infection — I can’t think of one!"
That doesn't match my understanding from what you've said here. Can you think of any examples of vaccines that prevent disease without providing sterilizing immunity? If not, what is it about SARS-CoV-2 that makes you think our priors from previous vaccines might not apply?
I find Dr. Sax's answer on this--and the fact that it appeared in the NEJM without being corrected--very puzzling, because it's wrong. Pretty much every virologist who has seen that claim has been scratching their heads about it because numerous vaccines in routine clinical use have disease-attenuating effects without providing sterilizing immunity. I've seen a couple of Twitter threads about this today, because of how incorrect it seems to be.
For example, the influenza virus vaccine *can* provide protection from infection, but it doesn't always. However, even if it does not provide protection from infection it is known to provide a spectrum of protection from disease, eliminating it entirely or lessening its severity.
The inactivated polio vaccine (IPV) is known to prevent conversion of polio infection from a gut infection to a neurological disease. It doesn't prevent infection by polio in the gut.
The herpes zoster vaccine also doesn't prevent infection, as I understand it, but generally this vaccine is used in people who are already infected in order to prevent symptomatic disease (shingles) in the case of virus reactivation.
If we go into the realm of bacteria, there are additional vaccines in widespread clinical use that prevent disease without preventing infection, but I'd rather stay in my lane of viruses since I've described enough examples already, all of them in widespread clinical use.
Another problem with this answer is that it doesn't actually matter whether the vaccine prevents infection or not, at least not for the purposes of answering this question. It seems like Dr. Sax is conflating infectivity with transmissibility, which isn't correct. Just because a virus can infect a host does not mean that that host can then spread the virus again. The issue being addressed by the question is whether the vaccinated host can spread the virus again, not whether they can be infected with it. It's true, though, that a vaccine which causes sterilizing immunity (prevention of infection entirely) will also prevent transmission, because the virus never infects and never replicates. What is less clear is whether, in the absence of sterilizing immunity, the virus can still be transmitted from the host.
The best example of this situation is with the IPV, where immunity is not sterilizing and people who have received the vaccine can very much play host to, and continue to transmit, the polio virus. It's a real thing and I'm surprised an infectious disease doc like Dr. Sax is unaware of it. Perhaps he is not aware of it because he largely practices in the US, where polio has been eradicated. This eradication is actually part of the reason that the US switched from administering oral polio vaccine to now using IPV; since the virus is no longer actively transmitting in the US, IPV is considered a safer option. The oral polio vaccine has a chance of reverting and causing polio in some patients.
We really just don't know the answer to this in the context of SARS-CoV-2. I believe it is likely that there is an effect on transmission in the context of these vaccines, but without data I am giving you a hypothesis, and I've had a lot of hypotheses in the past that have not borne out in the data.
Let's explore the hypothesis, though. First, we have to imagine two possible conditions. (1) The vaccine provides sterilizing immunity; in this situation, there is never an infection and so disease and transmission are bother prevented (2) The vaccine prevents the virus from causing disease by controlling the infection; sterilizing immunity is not achieved
(2) is a situation that could be caused by a number of different effects. It could be that disease is mostly mediated by an immune overreaction and when immune memory is present, that effect is reduced but the virus still replicates adequately to spread. We know that this situation is possible because we have evidence of people who are asymptomatic being able to transmit SARS-CoV-2 to others. So it's not beyond the realm of possibility that we have created more asymptomatic carriers with this vaccine. On the other hand, control of the disease may be achieved through an immune response that reduces the overall replication of the virus, and thus prevents transmission as well. This also seems fairly plausible.
As I've said in the past, I think it's also possible that the vaccine causes some kind of intermediate state--disease is no longer possible, and the capacity for transmission is reduced but not totally eliminated. I mention this possibility because it's important to realize that very few biological processes are binary. There is usually a continuum of possible states that exist between two potential extremes. This is one reason we need data on the ability of the vaccines to prevent transmission.
Back to the subject at hand: Due respect to Dr. Sax, I think he just gave a bad answer here. We all do that sometimes. He was asked about transmission and he answered about infection. Worse, he answered incorrectly about infection. I think that NEJM should retract the post. it's causing confusion and it doesn't contain accurate information.
There are at least two vaccines in development administered as nasal sprays (one from China, one developed by Lancaster University in England, in association with a the Biomedical Research Institute in Texas). Presumably nasal spray vaccine would induce an IgA response and be more likely to block infection, as opposed to "merely" disease.
In theory, yes, nasal spray vaccines ought to induce an IgA response. But of course, we need testing of each vaccine to demonstrate that this is the case. I'd love for that to happen and be successful. I'm sure that's underway.
Hey, John, have you written about antivirals? A diet of all vaccine essays is probably getting dull, and I find it disappointing that we still have no effective antiviral medications against SARS-CoV-2. (No, I don't think that remdesivir is actually doing anything.)
I wrote a couple of things about antivirals in the past, but I haven't in awhile. I'm not sure how I feel about remdesivir. I think its early clinical trial performance made sense in a systemic way but not on an individual patient basis.
I can write a little more about antivirals in coming days. Personally I do not think antivirals in a traditional sense are even half as useful as vaccines. Antivirals often don't perform the way we would hope--even eliminating 90% of the virus culture in a laboratory experiment often translates to very weak clinical benefits.
However, I do think some of the results with polyclonal antibody cocktails have been impressive. And the research involving steroid use has been very interesting as well. When a news story pops up on this I'll try to give it some coverage. Thanks for the suggestion.
I'm only aware of one disease where antivirals are really effective, namely AIDS/HIV infection. Not only are there effective treatments, there are not one, but two effective preventative meds. I'm sure you know orders of magnitude more than I do.
There are two viral diseases that come to mind for me. The important part here is that both are for chronic viral illnesses, which I think changes the dynamic of the situation.
You've mentioned one of the two, but I think it's worth noting that these antivirals for HIV are not curative. They vastly extend patient lifespan, but if discontinued the infection will once again take over. It is also possible for resistance to evolve, requiring a change in drug regimen.
The other is hepatitis C virus, which can actually be cured by antiviral agents. That was an amazing achievement that has really reduced the need for liver transplants around the world.
There are some other antiviral options that are somewhat effective against various infections but very little that compares to these two examples. Biologic rather than small molecule approaches have recently been pretty effective in a few virus-treatment situations, though. Regeneron, known for its COVID-19 antibody drug, also developed something similar for ebola virus that has really improved survival rates from that virus. I suspect that biologic approaches to antiviral treatment are going to be an area of expanded research in the future after these successes.