A fourth mRNA dose has been underway in Israel for a few months now. The U.K. recently started a fourth dose for people over 75 years old and coined it “spring boosters.” In Germany, those over 70 years old are eligible for a fourth shot of the mRNA series.
@Katelyn, a couple of thoughts and a couple requests.
Requests first: Do you have any citations I can snag on immune coverage for BA.2 derived from natural infection from BA.1? I've read several studies that I interpret in one manner but a JHU Public Health On Call podcast and their expert in that interview interpreted things differently. I'm also interested in any of the other Israeli studies on 4th-dose effect, as I recently saw one where they appeared to determine that a 2nd boost of Pfizer provided little benefit in young healthcare workers.
And, thoughts.
- Are we solely worried about circulating neutralizing antibodies, or have we settled on this because IgG is easier for the public to understand? What happened to B- and T-cell immunity and training the cellular immune system as a longer-term solution to the problem? I submit we can't keep up the cycle of repeat vaccination to maintain circulating immunity, especially now that we're seeing pharmacologic treatments that can be used without hospitalization in symptomatic individuals successfully
- The recent look at immunity afforded neonates via maternal immune response to infection as well as vaccination was interesting, especially a side note that most of the antibody response across the placenta was IgA vs IgG. I'm looking forward to the IgA -inducing vaccines.
- I continue convinced that our initial strategy of 2nd doses within 30 days of first doses of the initial dose for mRNA and likely adjuvant-vector vaccines was a shotgun approach to rapidly running up circulating IgG but failed to provide adequate time to "train" the cellular system, and failed to prime the humeral system for longer-term of circulating antibodies specific to the vaccine. Perhaps this is 20/20 hindsight but I wish we could have used a longer interval. I am now suspicious that our rapid waning of boosting doses was due that initial dosing regimen, and that we'd have seen something different if we'd been able to do second mRNA doses at 60 or 90 day intervals. Of course, it's been a long time since my immunology course work... but I'm trying to catch up.
- The issue with trying to come up with responsive variant-specific vaccines is the time it takes to ramp up production after you have a sequence. And anticipatory mRNA entries are likely to be wrong, driving up costs. In other words, we can create a new vaccine responsive to a new variant after A) the variant is identified, B) the variant is determined to be significant ("of concern" or "of high concern"), C) the variant is sequenced and the sequence distributed. Because we generally look at the Spike protein, we know where to go for changes but evaluating which of the myriad changes are significant is tedious. Almost easier to create a new mRNA responsive vaccine to the new S1/RBD elements than to try to determine which ones are at issue for vaccine evasion, transmission improvement or invoking serious disease, but inefficient in that a shotgun approach isn't enduring.
Thanks, as usual, for the update and assembling so much information in one spot.
Any idea why Israel all-cause mortality has been so high in 2022 so far? This is not a backhanded diss at the 4th shot - I am curious if you are aware of anything causing their deaths to be so highly elevated (I'm not seeing this trend in other countries).
Their excess deaths are incredibly high given the data we have from mortality.org (it lags quite a bit, so only have complete view of January and most of February, but expect weeks 6-8 to continue to rise as back-dated data comes in). They typically average 970 deaths/week with previous peaks as high as 1100-1200... yet now seeing upwards of 1300-1500 deaths/week.
Also, I am extremely frustrated at the cutting of funding. My hope was that this crisis would lead up to better focus on public health funding when we are in a non-crisis mode. That gives us time and energy to do all the things you talk about in this post and explore the best way to deal with things when we don't have an emergency breathing down our neck, but it sounds like it will yet again become a one crisis to another approach.
Thank you, as always, for your wonderful analysis. I wish vaccine and booster effectiveness studies would break out results by whether a person has had a past infection and natural immunity. I.e., maybe if you’ve never had Covid, you need a fourth shot; and if you have had Covid, the risks to getting a fourth shot outweigh the benefits.
Plus, I wish there was some thought to giving people who test positive therapeutics early on to prevent long Covid. Apparently even asymptomatics can suffer from long Covid.
It is clear from YLE March 25 update “Another mRNA Booster or Not?” that vaccine effectiveness was beginning to wane 5 ½ months after the 3rd shot. Whether or not to recommend a second booster is major concern since a fourth dose of the same thing would only be a short-term solution. YLE offers some excellent scientific challenges that may lead to a long term solution. I would like to suggest an intermediate term solution for consideration.
Covid Vaccine – Short Term Solution
Several months ago we were all focused on if, when and who should receive a booster. And we were smart/lucky, in that the “get boostered” switch was turned on in time for the Delta and Omicron surges.
Now, as per this March 25 update, we are once again, trying to figure out if, when and who should get a fourth dose/second booster.
Covid Vaccine – Long Term Solution
YLE is quite right when she says that “a fourth dose of the same thing would only be a short-term solution.” YLE lists 4 game-changer vaccine development strategies that need to be pursued: intranasal, variant-targeted, different biotechnology and pancoronavirus vaccine. Aggressive research to pursue these and other options will likely produce scientific breakthroughs in some of these areas within 2-5 years, perhaps sooner with intranasal and variant-specific vaccines.
But unless congress restores the covid preparedness appropriations that were removed a couple of weeks ago, it is unlikely that the fight against Covid will be a winnable battle sometime soon because it is not just the lack of research funding, but also not having financial support for the production and distribution of new vaccine technologies as well as public health surveillance.
Covid Vaccine – Intermediate Term Solution
I propose that the following intermediate term solution be considered – thoughts welcome:
Every 2, 3 or 4 months FDA receives applications from Pfizer and Moderna for a new vaccine dose/booster. Once EUAs are issued by FDA, it goes to CDC/ACIP for government policy defining who gets the next dose and when. Once this is done, reimbursement/payment follows. So since the initial 2-shot mRNA series with specific scheduling protocol, the booster and fourth shot appears to be scheduled on an ad hoc basis.
This has become more confusing as federal officials have been debating the “who” and “when” issue for the fourth dose. And now it appears that the government will soon be announcing that everyone 50 and older will have the option of getting a fourth dose without a specific recommendation to get it now or in the early fall. There are many legitimate issues concerning the timing of the fourth shot, but to the vaccine hesitant public, this undermines the “follow the science” mantra when government says “get it when you want”- the urgency seems wishy-washy.
I believe CDC/ACIP should consider establishing a guidance for a fixed vaccination schedule (FVS) of a booster shot for set time intervals (e.g. every 3 or 4 months) so that it is fixed in the public’s mind and PCPs. This continues as an intermediate term solution and as improved longer lasting or better targeted vaccines are approved, they would be introduced into the FVS with priority given to the immune compromised and older population(over 65 or 50?).
If there is a set schedule, it means you do not have to be concerned about whether to vaccinate now and not be protected for possible fall surge because with a set schedule you would be vaccinated now and in the early fall, with fifth shot (i.e. not one or the other) and thus, there would no longer be gaps in vaccine effectiveness.
It does not appear that repeated vaccinations induces resistant variants.
It does not appear that adverse vaccine reactions would be a major concern.
With only 66% of the U.S. population fully vaccinated and less than ½ that amount boostered, it would be important to have a well-structured Covid-19 vaccine delivery system in place with a well-understood FVS. You are either in the FVS or out of the FVS. Vaccine education initiatives could be directed to those not in FVS.
And until scientific breakthroughs lead to truly new generation vaccines, an FVS would allow us to do the best with the science we have now. Introducing the FVS concept to health care providers and consumers could be a prudent, timely and stable intermediate course of action to reduce morbidity and mortality until we come up with a silver bullet to better deal with covid in the long term.
Katelyn, Thank you so much for what you do. Breaking down all this info and putting it in understandable language is an enormous task. Again, thank you. Along with Bill above, I have had all 3 Moderna shots. But I am a little older (65) with asthma and a heart condition. Does it make sense to go with a 4th booster of J&J version of the vaccine?
Thank you for being sensitive to us J&J folks, in addition to all of the other information you provide. I received J&J vaccine in Spring 2021 and then decided to get a Moderna booster in Fall 2021. It's helpful to read your posts, as I evaluate my risk and ask myself: "can I consider my 2-shot protection to be the equivalent of a 3-mRNA dose protection?" So far, the answer seems to be a cautious "yes" and that helps me navigate situations more confidently.
I've seen some studies (I can't find the links, sorry!) about J&J providing longer duration protection (less waning). I've had 3 Moderna shots. Would it make sense to try for a J&J shot for my fourth one once that's approved? I'm a 55 year old male with no comorbidities.
Thanks again for excellent update re: 4 th dose need and timing. I wonder if there is data or guidance re: need for 4th dose for immunocompromized patients who received primary dose (I.e. full rather than 1/2 dose)?
Also, your point about the need for restoring govt funding is critically important . Sadly the current reprieve we have from the virus is lulling us to sleep. Failing to act to prepare for the next potential surge and/or new variant represents a real and present public health danger and risk to our economy.
Thank you for your dual focus on the science and public policy.
I am so grateful to you...you are truly a trusted voice. I am so lost right now. Public Health messaging no longer acts as a proxy for individual safety recommendations. While I care about hospital capacity, even more I want to know what is safe for my family to do or not do. It seems like my city has collectively shrugged its shoulders and decided the 2 year anniversary is the end date for any safety measures.. I don't want my kids (14 and 23) to get this, and I really, really want to protect my 85 year old father, but we are about the only ones still masking, and I worry about social consequences, too. They are boosted, but 6 months ago, so protection is waning. Is it worth the social consequences to be the only one in a room with a mask?
I have seen very little discussion about the impact of these vaccines on B cell immunity (memory cells). The B cells are important for long term immunity. Can you comment on this?
Many thanks Jetelina for helping us think through the Big Questions here, and - importantly - to improve our question-asking. For example, are we seeing the biological limits of immunizing into the circulation against a virus that enters through the respiratory tract? (in which case, as you point out, perhaps it will be super-important to use intranasal vaccine) Are our current mRNA vaccines too 'narrow-spectrum' (don't incorporate more parts of the virus needed for long-term effectiveness)? What evidence (or at least theoretical basis) do we have that (assuming it's available) a protein subunit vaccine would make a better booster than a fourth mRNA shot?
Thanks as always for such clear info. Can you comment on waning immunity after INFECTION? As opposed to (or actually concurrent with) vaccination and boosters. Omicron specifically. I am vaxed and boosted and almost three months out from Omicron infection, trying to gauge my vulnerability.
"Importantly, this study found that immunogenicity maxes out at 3 doses. In other words, there was no meaningful increase in the quality of the immune system after a fourth dose among the young population." I am 40 with PCOS and a son with asthma and am not sure in the value of a 4th dose. I am not asking for a personal rec, but want to understand if this means a 4th dose is maxed out for my age group.
@Katelyn, a couple of thoughts and a couple requests.
Requests first: Do you have any citations I can snag on immune coverage for BA.2 derived from natural infection from BA.1? I've read several studies that I interpret in one manner but a JHU Public Health On Call podcast and their expert in that interview interpreted things differently. I'm also interested in any of the other Israeli studies on 4th-dose effect, as I recently saw one where they appeared to determine that a 2nd boost of Pfizer provided little benefit in young healthcare workers.
And, thoughts.
- Are we solely worried about circulating neutralizing antibodies, or have we settled on this because IgG is easier for the public to understand? What happened to B- and T-cell immunity and training the cellular immune system as a longer-term solution to the problem? I submit we can't keep up the cycle of repeat vaccination to maintain circulating immunity, especially now that we're seeing pharmacologic treatments that can be used without hospitalization in symptomatic individuals successfully
- The recent look at immunity afforded neonates via maternal immune response to infection as well as vaccination was interesting, especially a side note that most of the antibody response across the placenta was IgA vs IgG. I'm looking forward to the IgA -inducing vaccines.
- I continue convinced that our initial strategy of 2nd doses within 30 days of first doses of the initial dose for mRNA and likely adjuvant-vector vaccines was a shotgun approach to rapidly running up circulating IgG but failed to provide adequate time to "train" the cellular system, and failed to prime the humeral system for longer-term of circulating antibodies specific to the vaccine. Perhaps this is 20/20 hindsight but I wish we could have used a longer interval. I am now suspicious that our rapid waning of boosting doses was due that initial dosing regimen, and that we'd have seen something different if we'd been able to do second mRNA doses at 60 or 90 day intervals. Of course, it's been a long time since my immunology course work... but I'm trying to catch up.
- The issue with trying to come up with responsive variant-specific vaccines is the time it takes to ramp up production after you have a sequence. And anticipatory mRNA entries are likely to be wrong, driving up costs. In other words, we can create a new vaccine responsive to a new variant after A) the variant is identified, B) the variant is determined to be significant ("of concern" or "of high concern"), C) the variant is sequenced and the sequence distributed. Because we generally look at the Spike protein, we know where to go for changes but evaluating which of the myriad changes are significant is tedious. Almost easier to create a new mRNA responsive vaccine to the new S1/RBD elements than to try to determine which ones are at issue for vaccine evasion, transmission improvement or invoking serious disease, but inefficient in that a shotgun approach isn't enduring.
Thanks, as usual, for the update and assembling so much information in one spot.
Any idea why Israel all-cause mortality has been so high in 2022 so far? This is not a backhanded diss at the 4th shot - I am curious if you are aware of anything causing their deaths to be so highly elevated (I'm not seeing this trend in other countries).
Their excess deaths are incredibly high given the data we have from mortality.org (it lags quite a bit, so only have complete view of January and most of February, but expect weeks 6-8 to continue to rise as back-dated data comes in). They typically average 970 deaths/week with previous peaks as high as 1100-1200... yet now seeing upwards of 1300-1500 deaths/week.
Screenshot of total deaths per week: https://imgur.com/a/XVeWwgf
Also, I am extremely frustrated at the cutting of funding. My hope was that this crisis would lead up to better focus on public health funding when we are in a non-crisis mode. That gives us time and energy to do all the things you talk about in this post and explore the best way to deal with things when we don't have an emergency breathing down our neck, but it sounds like it will yet again become a one crisis to another approach.
Thank you, as always, for your wonderful analysis. I wish vaccine and booster effectiveness studies would break out results by whether a person has had a past infection and natural immunity. I.e., maybe if you’ve never had Covid, you need a fourth shot; and if you have had Covid, the risks to getting a fourth shot outweigh the benefits.
Plus, I wish there was some thought to giving people who test positive therapeutics early on to prevent long Covid. Apparently even asymptomatics can suffer from long Covid.
Since so many of us 65+ folk had Omicron break through after booster, how should we considered that w.r.t. need and/or timing of 4th shot?
It is clear from YLE March 25 update “Another mRNA Booster or Not?” that vaccine effectiveness was beginning to wane 5 ½ months after the 3rd shot. Whether or not to recommend a second booster is major concern since a fourth dose of the same thing would only be a short-term solution. YLE offers some excellent scientific challenges that may lead to a long term solution. I would like to suggest an intermediate term solution for consideration.
Covid Vaccine – Short Term Solution
Several months ago we were all focused on if, when and who should receive a booster. And we were smart/lucky, in that the “get boostered” switch was turned on in time for the Delta and Omicron surges.
Now, as per this March 25 update, we are once again, trying to figure out if, when and who should get a fourth dose/second booster.
Covid Vaccine – Long Term Solution
YLE is quite right when she says that “a fourth dose of the same thing would only be a short-term solution.” YLE lists 4 game-changer vaccine development strategies that need to be pursued: intranasal, variant-targeted, different biotechnology and pancoronavirus vaccine. Aggressive research to pursue these and other options will likely produce scientific breakthroughs in some of these areas within 2-5 years, perhaps sooner with intranasal and variant-specific vaccines.
But unless congress restores the covid preparedness appropriations that were removed a couple of weeks ago, it is unlikely that the fight against Covid will be a winnable battle sometime soon because it is not just the lack of research funding, but also not having financial support for the production and distribution of new vaccine technologies as well as public health surveillance.
Covid Vaccine – Intermediate Term Solution
I propose that the following intermediate term solution be considered – thoughts welcome:
Every 2, 3 or 4 months FDA receives applications from Pfizer and Moderna for a new vaccine dose/booster. Once EUAs are issued by FDA, it goes to CDC/ACIP for government policy defining who gets the next dose and when. Once this is done, reimbursement/payment follows. So since the initial 2-shot mRNA series with specific scheduling protocol, the booster and fourth shot appears to be scheduled on an ad hoc basis.
This has become more confusing as federal officials have been debating the “who” and “when” issue for the fourth dose. And now it appears that the government will soon be announcing that everyone 50 and older will have the option of getting a fourth dose without a specific recommendation to get it now or in the early fall. There are many legitimate issues concerning the timing of the fourth shot, but to the vaccine hesitant public, this undermines the “follow the science” mantra when government says “get it when you want”- the urgency seems wishy-washy.
I believe CDC/ACIP should consider establishing a guidance for a fixed vaccination schedule (FVS) of a booster shot for set time intervals (e.g. every 3 or 4 months) so that it is fixed in the public’s mind and PCPs. This continues as an intermediate term solution and as improved longer lasting or better targeted vaccines are approved, they would be introduced into the FVS with priority given to the immune compromised and older population(over 65 or 50?).
If there is a set schedule, it means you do not have to be concerned about whether to vaccinate now and not be protected for possible fall surge because with a set schedule you would be vaccinated now and in the early fall, with fifth shot (i.e. not one or the other) and thus, there would no longer be gaps in vaccine effectiveness.
It does not appear that repeated vaccinations induces resistant variants.
It does not appear that adverse vaccine reactions would be a major concern.
With only 66% of the U.S. population fully vaccinated and less than ½ that amount boostered, it would be important to have a well-structured Covid-19 vaccine delivery system in place with a well-understood FVS. You are either in the FVS or out of the FVS. Vaccine education initiatives could be directed to those not in FVS.
And until scientific breakthroughs lead to truly new generation vaccines, an FVS would allow us to do the best with the science we have now. Introducing the FVS concept to health care providers and consumers could be a prudent, timely and stable intermediate course of action to reduce morbidity and mortality until we come up with a silver bullet to better deal with covid in the long term.
Katelyn, Thank you so much for what you do. Breaking down all this info and putting it in understandable language is an enormous task. Again, thank you. Along with Bill above, I have had all 3 Moderna shots. But I am a little older (65) with asthma and a heart condition. Does it make sense to go with a 4th booster of J&J version of the vaccine?
Thank you for your thoughts.
Bob.
Thank you for being sensitive to us J&J folks, in addition to all of the other information you provide. I received J&J vaccine in Spring 2021 and then decided to get a Moderna booster in Fall 2021. It's helpful to read your posts, as I evaluate my risk and ask myself: "can I consider my 2-shot protection to be the equivalent of a 3-mRNA dose protection?" So far, the answer seems to be a cautious "yes" and that helps me navigate situations more confidently.
In consideration of this teaser J&J news at the end
> Data continues to show that a J&J + 1 booster is working as well as the mRNA three dose series.
Are you aware of anyone studying a followup that would use a J&J as a booster after an initial mRNA round?
I've seen some studies (I can't find the links, sorry!) about J&J providing longer duration protection (less waning). I've had 3 Moderna shots. Would it make sense to try for a J&J shot for my fourth one once that's approved? I'm a 55 year old male with no comorbidities.
Thanks again for excellent update re: 4 th dose need and timing. I wonder if there is data or guidance re: need for 4th dose for immunocompromized patients who received primary dose (I.e. full rather than 1/2 dose)?
Also, your point about the need for restoring govt funding is critically important . Sadly the current reprieve we have from the virus is lulling us to sleep. Failing to act to prepare for the next potential surge and/or new variant represents a real and present public health danger and risk to our economy.
Thank you for your dual focus on the science and public policy.
I am so grateful to you...you are truly a trusted voice. I am so lost right now. Public Health messaging no longer acts as a proxy for individual safety recommendations. While I care about hospital capacity, even more I want to know what is safe for my family to do or not do. It seems like my city has collectively shrugged its shoulders and decided the 2 year anniversary is the end date for any safety measures.. I don't want my kids (14 and 23) to get this, and I really, really want to protect my 85 year old father, but we are about the only ones still masking, and I worry about social consequences, too. They are boosted, but 6 months ago, so protection is waning. Is it worth the social consequences to be the only one in a room with a mask?
I have seen very little discussion about the impact of these vaccines on B cell immunity (memory cells). The B cells are important for long term immunity. Can you comment on this?
Many thanks Jetelina for helping us think through the Big Questions here, and - importantly - to improve our question-asking. For example, are we seeing the biological limits of immunizing into the circulation against a virus that enters through the respiratory tract? (in which case, as you point out, perhaps it will be super-important to use intranasal vaccine) Are our current mRNA vaccines too 'narrow-spectrum' (don't incorporate more parts of the virus needed for long-term effectiveness)? What evidence (or at least theoretical basis) do we have that (assuming it's available) a protein subunit vaccine would make a better booster than a fourth mRNA shot?
Thanks as always for such clear info. Can you comment on waning immunity after INFECTION? As opposed to (or actually concurrent with) vaccination and boosters. Omicron specifically. I am vaxed and boosted and almost three months out from Omicron infection, trying to gauge my vulnerability.
Can you Please explain this a little more?
"Importantly, this study found that immunogenicity maxes out at 3 doses. In other words, there was no meaningful increase in the quality of the immune system after a fourth dose among the young population." I am 40 with PCOS and a son with asthma and am not sure in the value of a 4th dose. I am not asking for a personal rec, but want to understand if this means a 4th dose is maxed out for my age group.