Coronavirus updates April 2022

[missy]

State of Affairs: April 1

The impact of BA.2 in Europe has been consistent with a second case wave in almost every country. Each country’s current location on that wave is very different, though. For example, cases are increasing in France, stalling in the U.K., and falling in Germany, Switzerland, and the Netherlands.

yourlocalepidemiologist.substack.com

"

The impact of BA.2 in Europe has been consistent with a second case wave in almost every country. Each country’s current location on that wave is very different, though. For example, cases are increasing in France, stalling in the U.K., and falling in Germany, Switzerland, and the Netherlands.

Unfortunately, hospitalizations and deaths continue to lag as well. In fact, U.K. hospital admissions among 65+ year olds have passed their January peak.

​

UK hospitalizations by age (Colin Agnus)
The older age groups have the lowest prevalence of infection and the highest rate of vaccination, and data continues to show that about half of hospitalizations are “for COVID.” How could they be breaking hospitalization records? Vaccines could be waning, but recent data has shown this isn’t drastic. This could be attributed to behavior change: with restrictions lifted, older age groups could have recently and substantially changed their behavior after two years. But, more likely, the vulnerable are getting swept up in high community transmission. Vaccines work very well, but they’re not perfect. Even if vaccines were 95% effective against hospitalization, a small percentage change can become a big number when a virus burns through entire populations. We saw this happen in Denmark, too: during their BA.2 case surge, excess deaths were significantly higher for those aged 85+ years regardless of their almost 100% vaccination rate. This is one reason why a “let it rip” approach is so risky.

Because hospitalizations are increasing, deaths are increasing, too. In fact, in the U.K. they are quickly accelerating.

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United States
BA.2 is now the dominant variant in the U.S., making up 55% of new cases. This is up 39% from the week before. Prevalence ranges from 37% in the Midwest to 73% in the Northeast. Genome sequencing shows that case growth is right on track with projections. If this trajectory continues, we’ll see about 40,000 new cases per day by mid-April. How big this wave will be is anyone’s guess.

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(Source JPWeinland)
On a national level, some of our early indicators are beginning to feel BA.2’s presence. Test positivity rates (TPR) from PCRs and antigen tests have started increasing. Wastewater as a whole is remaining relatively stable.

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Purple= Midwest; Orange= Northeast; Pink=South; Green=West (Source Biobot Analytics)
Reflective of the early national indicators, national case trends have stalled; they are neither decreasing or increasing. Importantly, they stalled at relatively low daily case rates (27,621 new cases per day). Our lowest record was 14,000 cases per day in summer 2021; our highest was 800,000 cases per day during Omicron. Starting at a low case count will no no doubt help soften the impact of BA.2.

​

(Our World In Data)
As we’ve seen throughout the pandemic, the story is different on state and local levels. Last week only one state (New York) had increasing case trends. Now, we have 15 states: New York continues to be the acceleration leader, with a 55% increase in cases in the past 14 days.

When cases are so low after a massive wave it’s imperative that we look at raw case graphs and log case graphs. To the naked eye, cases can look stagnant but acceleration is happening. New York City, for example, seems to have a flat case rate (left graph below) but cases are increasing very quickly (right graph below). The R(t) in NYC is now around 1.5 and cases are being driven by the younger age groups.

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(Graphs by Conor Kelly)

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(New York City Health)
Cases are also increasing in other Northeastern states: Massachusetts (+48%), New Jersey (+37%), DC (+35%), Connecticut (31%), Delaware (+29%), Vermont (+6%), and Maryland (+6%). Mostly minimal changes. Local wastewater trends are trying to figure out what to do, too. In Boston, for example, we are seeing the beginning of exponential growth in the North system. But, the South system has minimal growth so far. Wastewater in New Haven, CT is mostly stable, too. This can change fast, though.

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In good news, this Tuesday we reached a huge milestone: the lowest number of hospitalizations since the pandemic began. This is a reason to celebrate, no matter how short this lull may or may not be.

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(Newsnodes)
This week we also finally broke the threshold of 1000 deaths per day. Today we are averaging 700 people dying per day. While this is incredibly welcome news, the majority of these are still vaccine-preventable. As Kaiser Family Foundation recently published, COVID-19 was still the second leading cause of death last month.

​

Bottom line​

BA.2’s footprint in the U.S. is starting to show. National indicators are pretty steady right now, but this can change quickly. Will it be a wave? We don’t know. But it doesn’t really matter if you prepare: get boosted, have a plan to get post-infection treatment, like Paxovid, order free antigen tests, and start wearing masks if county cases are increasing.



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[missy]

Kids' COVID Vax Mostly Holds Up Against Omicron Where It Counts​

— Lower protection than versus Delta, but still limits most severe forms of disease​

by Lei Lei Wu, Staff Writer, MedPage Today March 30, 2022

"
The Pfizer/BioNTech COVID-19 vaccine was less effective against the Omicron than Delta variant in children and adolescents, a multi-center study suggested.

During Omicron, vaccine effectiveness (VE) in those ages 12 to 18 years was 40% (95% CI 9-60) against COVID-related hospitalization and 79% (95% CI 51-91) against critical cases, according to Manish Patel, MD, MSc, of the CDC in Atlanta, and colleagues.

While during the Delta wave, VE was 92% (95% CI 89-95) and 96% (95% CI 90 to 9, respectively, they reported in the New England Journal of Medicine.



In children ages 5 to 11 years, VE against hospitalization during Omicron was 68% (95% CI 42-82), lower than might be expected when compared to how the vaccine performed (against infection) in a randomized trial conducted prior to the Omicron period, noted Patel and colleagues.

"Our study provides strong evidence for the benefits of vaccination in preventing the most severe forms of disease related to the Delta and Omicron variants in children and adolescents," they said.

When the group analyzed time since vaccination, among those 12 to 18, they found that VE against hospitalization remained relatively similar even months after vaccination. During the Delta period, VE was 93% in the 2-22 weeks after full vaccination and 92% at 23-44 weeks. During Omicron, VE was lower but also remained stable, at 43% (2-22 weeks) and 38% (23-44 weeks).

"The sustained protection in the analysis according to time since vaccination during the Delta and Omicron periods among adolescents 12 to 18 years of age, with an overall lower effectiveness during the Omicron period, suggests that evasion of immunity contributed more to the decline in protection than waning immunity," Patel and colleagues wrote.



Previous studies done in adult populations found similarly reduced protection from the Pfizer/BioNTech vaccine against Omicron.

Studies on VE can help determine "whether observed declines are related to waning protection that would be bolstered by booster doses of current vaccines (or increasing antigen content) or are instead related to immune evasion, which might require other strategies, such as updates to the vaccine strain," Patel and colleagues said.

The current study did not evaluate booster effectiveness in children since they were only recently approved for children ages 12 to 15, the researchers said.

The study included 2,812 children, 26% of whom were fully vaccinated. COVID patients as well as their matched COVID-negative controls were from 31 pediatric hospitals from 23 U.S. states. Case patients were those hospitalized with COVID-19 as their primary reason for admission or with symptoms consistent with COVID-19 and who had a positive PCR test. Patients were excluded if they were vaccinated 0 to 13 days prior to symptom onset, admitted to the hospital for other reasons, or received a booster dose.



Of the 1,185 COVID patients, one quarter had critical COVID-19 and 14 died. Just over 90% of those with critical COVID were unvaccinated. Broken down by age group, 918 of the COVID patients were ages 12 to 18 years (median 16) and 267 were ages 5 to 11 years (median .

For the older group with COVID, 684 were admitted during the Delta period, 234 during the Omicron period, and 78% had at least one underlying health condition. For the younger group, who were only studied during the Omicron period, 82% had at least one underlying condition.

The researchers noted they had limited follow-up time for the children ages 5 to 11, as vaccines were only approved in late October 2021 for this age group.
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[missy]

"

A Covid déjà-vu​

When Pfizer revealed the efficacy of its Covid pill last November, the excitement was palpable. Scientists hailed Paxlovid as a breakthrough. World leaders raced to lock up supplies. But just three months into the rollout, optimism about the drug’s ability to help bring a swift end to the pandemic is waning, as fears mount that unequal distribution will exacerbate the challenge of getting the virus under control. It’s too soon to say whether this will end up being as inequitable as the botched deployment of Covid vaccines. Mass quantities of the therapy may take more than a year to become available because of production and regulatory hurdles, according to drug experts. After wealthy nations snapped up a large share of initial supplies of Paxlovid, which slashed the risk of hospitalization and death from Covid-19 by 89% in clinical trials, many low- and middle-income countries are facing a potentially long wait for generic versions. “We’ve already had those discussions with vaccines,” says Borna Nyaoke-Anoke, a doctor and researcher in Kenya with the Drugs for Neglected Diseases Initiative, a nonprofit. “It’s quite unfortunate that we need to have them again.” Paxlovid antiviral medication. Photographer: Kobi Wolf/Bloomberg With thousands of Covid deaths a day, time is the one thing the world doesn’t have. Whenever the virus starts to subside, new variants or subvariants pop up, causing fresh spikes in cases. Knowing the critical role Pfizer’s drug could play in saving lives, health organizations, researchers, and companies are working to accelerate production beyond current forecasts and bring down the high cost of manufacturing. African health officials are acutely aware of what’s at stake, with the scramble for Covid drugs. More than two decades before the pandemic, the high price of HIV drugs sparked an outcry as millions in Africa and other regions who couldn’t afford the treatments died. “A global disease became a lower- and middle-income country disease, or an African disease, because we did not have the capacity to be able to have adequate treatment,” says Nyaoke-Anoke, the Kenyan researcher. “The same thing could happen with Covid.” — James Paton :

 

[dk168]

Second booster has started to be rolled out in March 2022 for the over 75s and extremely vulnerable people.

I personally know of multiple people in my different social circles getting Covid despite being triple-vaccinated. However, they all reported mild flu/cold like symptoms, with only 1 person suffering from Long Covid.

I have fully recovered from Covid myself, and have stopped performing 2-weekly lateral flow tests. I am saving the residual LFTs to test if I have Covid when I am ill.

I do not know if or when I would be called up to receive the second booster/4th dose of vaccine, and when I get the call, I shall definitely have it.

Living with Covid the best I can, pretty much back to normal except for foreign travel with nothing planned for the remainder of 2022.

DK

 

[AnastasiaBeaverhausen]

Just saw this and had to share. Apparently there's 9 new symptoms listed on official list of COVID symptoms.

Nine new Covid symptoms added to official list - BBC News

Sore throats, headaches and loss of appetite are now all officially recognised as signs of infection.

www.bbc.com

For the last one, they put "feeling sick or being sick."

Gee thanks, Captain Obvious

 

[Snowdrop13]

I know more people who are testing positive than ever before! There were 4 people off last week from my workplace alone. We are still isolating for 10 days if positive but that rule is likely to change soon.

I haven’t had it but I think it’s time to start living again. I went to the theatre last week, it was all very civilised, everyone being respectful and wearing a mask. I felt pretty safe.

 

[mellowyellowgirl]

I went to a wedding where everyone had no masks and it felt like normal!

We have some deadly mosquito disease here now so people were more alarmed about mozzies than Covid. There was a lot of mozzie avoidance and people looking around worried when they were outside. Most of them have already had Covid!

 

[Dandi]

Well Rona has finally hit our house...and wow, it really sucks! Both of my kids and I are positive, they had a runny nose for 24 hours and are back to normal, but I feel absolutely revolting, I haven't been this unwell in years. I'd hate to think how I might feel had I not had my booster. Hubby has managed to avoid it so far.

 

[missy]

Mixed Bag for Fourth Dose of Pfizer Vaccine vs Omicron​

— Real-world data show less infection and severity, but long-term benefit less clear​

by Molly Walker, Deputy Managing Editor, MedPage Today April 5, 2022

"

Rates of confirmed Omicron-related COVID infection and severe disease were lower after a fourth dose of the Pfizer-BioNTech vaccine, according to real-world data from Israel, although protection against confirmed infection seemed short-lived.

Among adults ages 60 and up, the adjusted rate of confirmed infection 4 weeks after the fourth dose was twice as low compared to those who received three doses (171 vs 340 cases per 100,000 person-days), reported Yair Goldberg, PhD, of Technion-Israel Institute of Technology in Haifa, and colleagues.



Moreover, the adjusted rate of severe illness after 4 weeks was three times lower in the four-dose group (1.6 vs 5.5 per 100,000 person-days), they wrote in the New England Journal of Medicine.

Adjusted rates of both infection and severe disease were both higher in a third "internal control" group, who received a fourth vaccine dose only 3 to 7 days earlier (308 and 3.6 cases per 100,000 person-days, respectively), they noted.

However, Goldberg and colleagues added that from week 5 onward, the rate ratio for confirmed infection began to decline, with the adjusted rate of infection 8 weeks after the fourth dose being "very similar to those in the control groups."

The authors concluded that a fourth dose provided "only short-term protection and a modest absolute benefit," for confirmed infection, but that it did increase protection against severe disease. They highlighted that "protection against severe illness did not appear to decrease by the sixth week after receipt of the fourth dose," but acknowledged that "More follow-up is needed in order to evaluate the protection of the fourth dose against severe illness over longer periods."



In January, Israeli authorities approved a fourth dose of Pfizer vaccine for adults ages 60 and up, high-risk populations, and healthcare workers, 4 months after a third dose, they noted. FDA recently authorized a second booster dose of Pfizer or Moderna vaccine for adults, ages 50 and up, and those with immunocompromising conditions, in part using real-world Israeli data as the basis for their decision.

Goldberg's group examined data on adults ages 60 and older who received three doses of Pfizer at least 4 months prior to the end of the study. The study period was defined as January 10 to March 2 for confirmed infection, and until February 18 for severe disease. The four-dose group completed their fourth dose at least 8 days prior to infection or severe COVID, they said.

Overall, 1,252,331 adults were included in the study, with 623,355 receiving four doses of vaccine and 628,976 not receiving four doses of vaccine. The aggregated four-dose group and internal control group had more person-days over age 80 (about 25% apiece vs 16.2%).



At 4 weeks, the adjusted rate of confirmed infection in the four-dose group was lower by a factor of 2.0 (95% CI 1.9-2.1) versus the three-dose group and lower by a factor of 1.8 (95% CI 1.7-1.9) versus the internal control group.

For severe disease at 4 weeks, the adjusted rate differences were 3.9 fewer cases per 100,000 person-days (95% CI 3.4-4.5) versus the three-dose group and 2.1 fewer cases per 100,000 person-days (95% CI 1.4-3.0) versus the internal control group.

Limitations to the data include unmeasured confounders, such as behavioral differences between adults who chose to receive the fourth dose and those who did not. Pre-existing conditions could have affected risk for severe disease, and the authors added they did not adjust for those as this information is not available in the national database. Different COVID treatment may have also affected the results, they noted.




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[missy]

Well Rona has finally hit our house...and wow, it really sucks! Both of my kids and I are positive, they had a runny nose for 24 hours and are back to normal, but I feel absolutely revolting, I haven't been this unwell in years. I'd hate to think how I might feel had I not had my booster. Hubby has managed to avoid it so far.

Wishing you all a speedy and full recovery @Dandi

 

[missy]

"

A new mystery​ ​

To many people’s surprise — including mine — new Covid-19 cases in the U.S. have not begun to rise. Over the past two weeks, they have held roughly steady, falling about 1 percent, even as the highly contagious BA.2 subvariant of Omicron has become the dominant form of Covid in the U.S.​

Across much of Europe, by contrast, cases surged last month after BA.2 began spreading there, and many experts expected a similar pattern here. That hasn’t happened. “It has not taken off,” Michael Osterholm, a University of Minnesota epidemiologist, told me.​

Chart shows 7-day averages as of April 4. | Sources: New York Times database; Johns Hopkins University​

What’s going on? Today’s newsletter looks at four possible explanations.​

1. More immunity​ ​

Even though the U.S. has a lower vaccination rate than Western Europe, this country may still have built up more immunity — thanks to our politically polarized response to the virus.​

In liberal parts of the U.S., vaccination rates can be even higher than in Europe. In conservative communities, many Americans have been so dismissive of Covid that they have long been living almost normally. As a result, the virus has already swept through these communities, conferring at least some immunity on many people.​

This laissez-faire approach has had horrible downsides. Covid death rates have been much higher in counties that voted for Donald Trump than those that voted for Joe Biden. But for people who survived a prior Covid infection, it does confer some immune protection, especially if it was recent.​

“Most of Europe has been pretty Covid averse,” William Hanage, a Harvard epidemiologist, said on a recent episode of the “In the Bubble” podcast, “whereas parts of the United States have been quite Covid curious.” Hanage said that he still expected U.S. caseloads to rise soon. But, he added, “I don’t think it’s going to be as dramatic as Europe.”​

If that’s correct, a preview is already visible in the Northeast, where cases have been rising lately, but not as steeply as in Europe.​

Chart shows 7-day averages. | Source: New York Times database​

One possible reason: There are not as many Americans vulnerable to infection. The earlier version of the Omicron variant seems to have infected about 45 percent of Americans, according to Andy Slavitt, a former Covid adviser in the Biden White House. That share appears to be higher than Europe’s.​

2. Fewer tests​ ​

The shift toward at-home testing in recent months means that a smaller share of actual Covid cases may be showing up in the data that government agencies report and news organizations like The Times publish. The government data relies on laboratory tests.​

Another potential factor depressing the volume of tests is reduced access for lower-income Americans. Some uninsured people now must pay for their own tests, and many testing clinics have closed.​

All of which raises the possibility that Covid cases really are surging now, even if the data doesn’t show it.​

Jessica Malaty Rivera of Boston Children’s Hospital told The Atlantic that the quality of current Covid data was “abysmal.” Dr. Scott Gottlieb, a former F.D.A. commissioner, told CNBC that he thought some parts of the country were “dramatically” underreporting cases.​

This chart suggests that underreporting is a real issue. As you can see, official testing in several European countries increased as BA.2 spread, while testing in the U.S. has declined modestly.​

Comparisons across countries are affected by different testing policies and reporting methods. | Source: Our World in Data​

Still, the shortage of testing does not seem to be the only reason that cases have not surged in the U.S. Trends in Covid hospitalizations typically lag case trends by only about a week. And hospitalizations have continued to fall in the U.S., to their lowest level in more than two years.​

3. Just wait​ ​

Even if high levels of immunity have kept cases from rising so far, the effect may not be permanent. Remember: About 45 percent of Americans were infected with Omicron, which leaves about 55 percent who were not. While many of those 55 percent may have had an earlier version of Covid, immunity can wane over time.​

The current moment might be one of those times when we’re asking why cases have not begun to rise right as they begin to rise. “It may be too early to see a signal,” Jennifer Nuzzo, a Brown University epidemiologist, told me.​

4. Another mystery​ ​

Throughout the pandemic, Osterholm — the Minnesota epidemiologist — has lamented that many scientists, journalists and laypeople exaggerate how much we actually know about Covid. His favorite example: The Alpha variant swept through Michigan and Minnesota last year and then largely died out, without causing case increases in other parts of the U.S. Another example: BA.2 has recently become the dominant variant in India, South Africa and some other countries without causing a spike in cases.​

When I called Osterholm yesterday to ask why cases had not surged over the past few weeks, he simply said: “I don’t know, and I don’t think anybody really knows.”​

Of all the variants, only the original Omicron was so contagious that it spread around the world in predictable ways, he said. Other versions of the virus have surged and receded in mysterious ways, much as a forest fire can die out without burning down an entire forest.​

The bottom line: Cases still seem likely to rise, perhaps significantly, in the U.S. soon. But a new wave looks less certain than it did a few weeks ago. Regardless, the steps that can save lives in coming months remain the same: more vaccine shots, including boosters; and greater awareness of available treatments that offer extra protection for the vulnerable. "​

 

[missy]

"

Original antigenic sin: Are boosters a threat?​

Katelyn Jetelina

Many are trying to decide whether to get another booster. In order to make this decision, benefits must be weighed with risks. More than 11.3 billiondoses of COVID19 vaccines have been distributed, so we are well aware that the vast majority of side effects are mild. Are there any other risks to getting another booster, like “original antigenic sin” (OAS)?
There has been considerable chatter among the public about OAS. From what I can tell, attention was sparked after an op-ed was published in the NYT before Omicron. A few clinicians, including Paul Offit, said:

“It’s (...) possible that repeatedly “training” the immune system to fight the original virus could reduce the effectiveness of a variant-specific booster. This phenomenon, called “original antigenic sin,” has been observed with influenza and human papillomavirus vaccines. In other words, for those not in immediate need of a boost, there may be a significant advantage to waiting until a booster more closely aligned with circulating variants becomes available; boosting on the original antigen could be counterproductive.”

OAS is one of the most complicated and misunderstood parts of an already complex immune system. I partnered with Edward Nirenberg to “translate” the science:

• What is OAS?
• What is the science saying about OAS for SARS-CoV-2?
• Is OAS a risk that should be weighed for a fourth booster?

Disclaimer: This post was incredibly difficult to write. My hardest since the pandemic began. It’s a very complex topic that even PhD immunologists get mixed up (and I’m an epidemiologist). This makes “translating” the topic even more difficult. I hope I don’t lose you. But if I do, just go to the “bottom line” section. Buckle up.

Original antigenic sin (OAS)​

When we come in contact with a virus or get a vaccine for the first time, our immune system develops a repertoire of tools. One of those tools is B-cells, which are antibody factories. Each B-cell makes a single antibody shape, and they can pump out huge quantities of antibodies if needed. If you come in contact with another variant, B-cells can evolve and modify the antibodies they create for a new variant. This is just like factories that can modify their product on the line.
The immune system wants to clear a threat in the fastest way possible. Responses based on memory (as opposed to modifying the antibodies) work fastest, so B-cells get to work pumping out antibodies of shapes they’ve seen before. This is called “imprinting.” Imprinting in and of itself is neither good nor bad. It simply reflects that a person's first exposure to a virus can have a noticeable effect on their later responses to variants of that same virus.
Original antigenic sin (OAS) is a special type of imprinting. In OAS, prior memory can interfere and even prevent you from generating antibodies against new variants. How this occurs is not well understood.
But we do know that OAS occurs with some other viruses, like the flu. For example, the first flu infection you get as a child has been shown to impact the way you react to flu variants later in life. While it could induce a less than optimal response, it can also be good and provide a more robust response. The figure below displays this phenomenon nicely.
Say a 2 year old is infected with the flu with A-D shapes on the virus. So, that child makes antibodies with A-D shapes. But then, at 5 years old, they are exposed to another variant with shapes A, C, E, and F. Because of the first exposure, only antibodies for shapes A and C respond. Even though there are only two shapes recognized, they provide a much stronger response than originally. Then, say at 20 years old, that same person is exposed to a virus with shapes A, D, E, and G. Because of the very first exposure (at 2 years old), antibodies A and D are recalled to fend off the infection; antibodies against E and G do not get made.

​

Figure 11.34 from Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. Boca Raton, FL: CRC Press; 2016
During the 1918 flu pandemic, we also saw very worrisome epidemiological signs of OAS. Those who were previously infected by the Russian flu (i.e. a different type of swine flu) did significantly worse during the pandemic than those not previously infected by the Russian flu.
Because we’ve seen OAS with other viruses, it’s theoretically possible with SARS-CoV-2. And scientific studies are now coming through.

What is the science saying?​

The best way to analyze OAS is to look at someone who has never been exposed to SARS-CoV-2 (including through vaccination) and infect them with Omicron. Then, compare their immune response to someone who has been vaccinated and gets a breakthrough case. To my knowledge, this type of study has not been conducted. So we have to rely on proxy studies and assess OAS indirectly. So far, results are mixed.
On one hand, there is some evidence of OAS with SARS-CoV-2:

• One scientific group found that exposure to coronaviruses (like the common cold) before the pandemic may impact our response to SARS-CoV-2. It’s important to note that there were significant internal inconsistencies with this study though.
• Another group found that monkeys with a Beta-specific or Omicron-specific booster had no extra protection compared to a regular formula booster. This was surprising because Omicron has 32 changes on its spike protein compared to the original virus. So, one would hypothesize that a vaccine with an updated spike protein would provide some sort of additional protection. OAS may explain why it’s not working. Importantly, there could be alternative explanations of why this is happening, too. For example, there may have not been enough follow-up time or Omicron or Beta may simply not be as good at driving the immune response.

Then there’s science showing OAS only with infection and not vaccination:

• One study found that SARS-CoV-2 infections caused B-cells to recall past coronavirus infection (like common cold) memory. But vaccines did not. This could be because of location: COVID19 is inhaled—as opposed to vaccines, which are introduced in the muscle—causing less affinity.

On the other hand, there is evidence that OAS is not a concern for SARS-CoV-2 among humans.

• An interesting study found OAS occurred in mice but not children. Specifically, scientists infected mice with the common cold and they were unable to make antibodies against SARS-CoV-2. On the other hand, scientists found that children with a history of this common cold were able to make SARS-CoV-2 antibodies.
• Most recently a team from BioNTech evaluated 3 vaccine doses+infection compared to 2 doses+infection. They found that those with the 3 doses+infection had a higher number of neutralizing antibodies and created Omicron-specific B-cell memory. This suggests an “expanded imprint”—prior memory did not interfere with generating antibodies against new variants. Importantly, though, some level of imprinting was still present, as the majority of memory B cells were those from the original vaccine.
• Data from a group of individuals in Stanford and Mongolia found that many COVID19 vaccines (not just mRNA) had extremely broad responses—significantly more so than those elicited by infection from specific variants, suggesting that the immune system has more paths of protection for new variants of concern.
• A French group tracked the antibody response against SARS-CoV-2 over time in humans. They found that while initially B-cells recalled cold coronaviruses, they were successively replaced with SARS-CoV-2-specific antibodies. This, again, argues against a substantial role for OAS.

Can another booster make OAS worse?​

It’s plausible that repeated boosting may make it harder to respond to future variants. Theoretically, repeated exposure to an older variant formula may drive our immune system to concentrate too much on old features and not on new features. But despite some truly surprising evolutionary leaps of the virus (like Omicron) we have not seen any convincing evidence of OAS among humans, which is great news.
In the event that OAS does prove to be a concern, there are tactics that vaccinology can take to work around it. For example, we are testing universal vaccines against SARS-CoV-2 and are fortunately seeing early promising results. Furthermore, flu scientists have found a way to boost immunity by targeting other areas of the virus. In a phase I study, scientists tested this strategy and OAS was not a problem for more than 1 year later.

Bottom line​

After two years of vaccines and the virus significantly mutating, there is no definitive evidence of OAS in humans being an important concern for COVID-19.
Without knowing the future, decisions must continuously weigh benefits with risks we know right now. Evidence from Israel shows meaningful benefit of a fourth mRNA dose (or second booster) against severe disease among older adults. We need to be responsive to the needs of our immune systems to protect us from this virus. The reality is, for someone who needs a booster, the theoretical concern of OAS is not a strong enough reason to not get it.

Bottom bottom line​

If you’re eligible, go get your booster.
Love, YLE and Edward Nirenberg

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[missy]

"

What’s the best Covid vaccine?​

Nine Covid-19 vaccines utilizing several design approaches have been listed for emergency use by the World Health Organization. Since they began rolling out in mass vaccination campaigns more than a year ago, people have asked, which shot is best? Public health officials typically say that the best is whatever one you’re being offered, since all the WHO-endorsed vaccines have been shown to protect against severe illness and death from Covid, and that rapid, mass immunization is the fastest way to end the pandemic. There’s also the fact that the immunological effects of each vaccine haven’t been directly comparable. That’s because measurements of virus-blocking antibodies and infection-fighting white blood cells called T cellsfrom vaccine recipients were taken by different laboratories using different equipment and methodologies from different groups of people at different time points. Researchers at California’s La Jolla Institute of Immunology have sought to even the playing field with the first side-by-side comparison of the four shots used in the U.S. made by Pfizer, Moderna, Johnson & Johnson and Novavax. The shots train the immune system to recognize the spike protein on the surface of the coronavirus using different approaches: messenger RNA (Pfizer and Moderna), a virus vector (Johnson & Johnson) and protein sub units (Novavax). Photographer: Kiyoshi Ota/Bloomberg Photographer: Kiyoshi Ota/Bloomberg In a paper released ahead of peer-review and publication last month, Daniela Weiskopf, Alessandro Sette and colleagues identified some differences, as well as commonality, in the immune responses of vaccine recipients six months after completing a standard immunization course. They found that all four vaccines induced antibodies that help protect against infection. Although anibody levels contract naturally over time, they can be bolstered within days thanks to blood cells that maintain “immune memory” of the coronavirus, Sette said. The La Jolla Institute study found the cellular response were “fairly stable” over time after all four vaccinations. Antibody levels were comparatively lower after vaccination with the Johnson & Johnson shot. Still, Weiskopf said it’s important to remember that, unlike the other vaccines, J&J’s is administered as a single shot, instead of a two-dose regimen. The J&J shot also triggered a different immune memory response among B cells, which make antibodies, though its significance isn’t fully understood yet, she said. All four vaccines generated so-called CD4 or “helper” T cells, but none was particularly good at sustaining high levels of CD8, or “killer,” T cells that recognize and destroy virus-infected cells. The findings will inform the design of future vaccines against other pathogens, Weiskopf said “We really are now able to compare, side by side, different vaccine platforms using the same antigen,” she said. “That hasn’t happened before for any other vaccine.” Still, many questions remain, including how well different vaccines protect against the constellation of lingering health problems known as long Covid, and whether different vaccine regimens can provide immune responses that are longer lasting or protective against a wider range of coronavirus variants. — Jason Gale "

 

[missy]

FDA Panel Mulls COVID Booster Issues Despite 'Insufficient' Data​

— Lack of data and open-ended questions from FDA frustrate members​

by Molly Walker, Deputy Managing Editor, MedPage Today April 7, 2022
"

All the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) could agree about on Wednesday in terms of a plan for COVID boosters is that they need more data.
The 8-hour meeting, broadcast over YouTube, was riddled with technical glitches early on, and ended with some frustration over the open-ended questions the agency posed.
FDA staff charged VRBPAC members with discussing what considerations should inform strain composition decisions for COVID boosters, how often should these be assessed, what would indicate a need for an updated strain composition, and what considerations should inform timing and populations for COVID boosters.

Members agreed that the focus of boosters should be preventing hospitalization and death, but they didn't feel comfortable with boosters every 8 weeks. They also seemed to settle on 80% protection from severe outcomes as an acceptable threshold for vaccine effectiveness. But questions about which data should inform booster selection, and timing of vaccination were more gray areas.
VRBPAC chair, Arnold Monto, MD, of the University of Michigan, also lamented the lack of a concrete proposal from the agency that the committee could respond to, specifically.
Monto began the discussion by saying evidence was "insufficient right now to give you in any way precise comments for all the discussion questions."
"How often should adequacy of strain composition of available vaccines be assessed? 'As often as you can,'" he said. "We really have to be very flexible in some of the conclusions we come to."
Michael Nelson, MD, PhD, of UVA Health and UVA School of Medicine in Charlottesville, Virginia, said he supported a "unified approach" for vaccine strain composition, but urged adopting "a framework that is more intentional" and involves "making changes only when we feel that the changes will lead to a longer duration" of protection.

"We need to use our predictive models and perhaps pivot to a multi-valent approach," he said, adding that future COVID boosters would perhaps be comprised of "historically based strains" and then "cautiously fold in future variants."
FDA staff, including Doran Fink, MD, PhD, agreed, saying it would also provide better coverage especially for those who might be getting the two-dose primary series for the first time.
"Pivoting towards a mono-valent vaccine runs the risk of narrow ... coverage for people getting the vaccine as a primary series," he said. "It seems at least to me to make a compelling case for any modifying vaccine ensuring breadth of coverage [and] able to handle whatever variant may come."
Ultimately, Monto said, "we would love to see an annual vaccination similar to influenza, but we realize the evolution of the virus will dictate how we respond in terms of additional vaccine doses."

VRBPAC members also lamented the lack of concrete correlates of protection. FDA's Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research, said that the agency is "working with NIH colleagues, trying to work through this."
In the absence of a clear correlate, however, he said they've been using "poor man's correlates," such as antibody levels.
Though VRBPAC members agreed that in an ideal world, they would like to see clinical data to inform decisions on boosters, Eric Rubin, MD, PhD, of Brigham and Women's Hospital in Boston, questioned if the timing for manufacturing would make that feasible.
"If we're going to do this in a timely fashion, we're going to have to use safety and immunogenicity as our endpoints and not clinical data," said Rubin, who is also editor-in-chief of the New England Journal of Medicine. "I just don't think it's going to be practical."

Marks indicated that FDA would need to decide by June if current vaccines were to be updated to target different strains for a fall booster.
Amanda Cohn, MD, of the CDC, addressed the question of protection, saying that CDC is doing multiple studies on vaccine effectiveness, but they're "never going to get the kind of specificity everyone would like to see."
She brought up a point, also hammered early on by Marks, that half of Americans have yet to receive a third dose, and cautioned not to just look at "relative [vaccine] effectiveness" as it can "misstate the overall protection the three-dose series does provide."
Monto backed up his support for an 80% vaccine effectiveness threshold by saying that with the "development of antivirals and therapeutics, you can't prevent everything with an evolving virus."
"The need for revaccination will be dictated by the virus more than by us," he noted.
Marks said that VRBPAC would meet again in early summer to discuss "more specific detail" regarding the composition of future boosters to "stay ahead of future variants and outbreaks" and promised "a fair number of meetings for this committee" in the future.
"

 

[missy]

"

Who really decides vaccine policy?​

When it comes to U.S. vaccination policy, who is in the driver’s seat? It’s up to officials at the Food and Drug Administration and the Centers for Disease Control and Prevention to authorize and lay out the standards for administering vaccines. But some experts have started to wonder aloudwhether vaccine makers have been framing the debate over whether and when to give more shots. “I feel like at some level, the companies kind of dictate the conversation,” said Paul Offit, a vaccine expert at the Children’s Hospital of Philadelphia, at a meeting of FDA advisers this week. “It shouldn’t come from them. It really has to come from us.” American culture is marked by epic rivalries between big corporations: McDonalds vs. Burger King. Coke vs. Pepsi. Ford vs. General Motors. Apple vs. Microsoft. But corporate sagas get more complicated when public health is on the line. Right now drugmakers Pfizer and Moderna are locked in a blow-for-blow battle over the market for messenger RNA shots. Both have to answer to their shareholders, and of late those shareholders haven’t been happy. Pfizer shares are off about 10% from a recent high in December, while Moderna shares have lost about two-thirds of their value since a peak in August. Each company has a lot riding on Covid-19 vaccines as a long-term franchise, but lots of open questions remain, and the data is thin. The battle for vaccine market share is part of a long history of American corporate rivalries, like between McDonald’s and Burger King. Photographer: Luke Sharrett/Bloomberg It’s as uncertain as ever just what the future of Covid shots might be. Europe is moving much more slowly to embrace boosters, even after an omicron wave that exposed how vulnerable society is to new variants. There, regulators have taken a more skeptical view of their utility. And in the U.S., the strain of a torrid cycle of shots over the past two years is starting to show. “The current situation where we are feeling compelled to boost every four months potentially is not sustainable,” said Mark Sawyer, a professor of pediatric infectious disease from the University of California in San Diego, who also serves on the FDA advisory panel. —Tim Annett "

 

[missy]

My best friend Tom has Covid. Despite wearing masks and getting both boosters. He was notified via phone he was exposed to an individual who had Covid. But only for a few minutes. Yet he came down with chills and fever and his rapid test was negative but his PCR positive this AM. Ugh.

 

[missy]

I don't remember if I shared this article. FYI

NEJM

Protection by a Fourth Dose of BNT162b2 against Omicron in Israel​

List of authors.

• Yinon M. Bar-On, M.Sc.,
• Yair Goldberg, Ph.D.,
• Micha Mandel, Ph.D.,
• Omri Bodenheimer, M.Sc.,
• Ofra Amir, Ph.D.,
• Laurence Freedman, Ph.D.,
• Sharon Alroy-Preis, M.D.,
• Nachman Ash, M.D.,
• Amit Huppert, Ph.D.,
• and Ron Milo, Ph.D.
• 
  
• April 5, 2022

"

BACKGROUND​

On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine to persons 60 years of age or older. Data are needed regarding the effect of the fourth dose on rates of confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and of severe coronavirus disease 2019 (Covid-19).

METHODS​

Using the Israeli Ministry of Health database, we extracted data on 1,252,331 persons who were 60 years of age or older and eligible for the fourth dose during a period in which the B.1.1.529 (omicron) variant of SARS-CoV-2 was predominant (January 10 through March 2, 2022). We estimated the rate of confirmed infection and severe Covid-19 as a function of time starting at 8 days after receipt of a fourth dose (four-dose groups) as compared with that among persons who had received only three doses (three-dose group) and among persons who had received a fourth dose 3 to 7 days earlier (internal control group). For the estimation of rates, we used quasi-Poisson regression with adjustment for age, sex, demographic group, and calendar day.

RESULTS​

The number of cases of severe Covid-19 per 100,000 person-days (unadjusted rate) was 1.5 in the aggregated four-dose groups, 3.9 in the three-dose group, and 4.2 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of severe Covid-19 in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 3.5 (95% confidence interval [CI], 2.7 to 4.6) and was lower than that in the internal control group by a factor of 2.3 (95% CI, 1.7 to 3.3). Protection against severe illness did not wane during the 6 weeks after receipt of the fourth dose. The number of cases of confirmed infection per 100,000 person-days (unadjusted rate) was 177 in the aggregated four-dose groups, 361 in the three-dose group, and 388 in the internal control group. In the quasi-Poisson analysis, the adjusted rate of confirmed infection in the fourth week after receipt of the fourth dose was lower than that in the three-dose group by a factor of 2.0 (95% CI, 1.9 to 2.1) and was lower than that in the internal control group by a factor of 1.8 (95% CI, 1.7 to 1.9). However, this protection waned in later weeks.

CONCLUSIONS​

Rates of confirmed SARS-CoV-2 infection and severe Covid-19 were lower after a fourth dose of BNT162b2 vaccine than after only three doses. Protection against confirmed infection appeared short-lived, whereas protection against severe illness did not wane during the study period.

During late December 2021, with the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, the prevalence of confirmed infection rose sharply in Israel. Some of the contributing factors were increased immune evasion by the variant1 and the passage of more than 4 months since most adults had received their third vaccine dose. In an effort to address the challenges presented by the omicron variant and to reduce the load on the health care system, on January 2, 2022, Israeli authorities approved the administration of a fourth dose of the BNT162b2 vaccine (Pfizer–BioNTech) to persons who were 60 years of age or older, as well as to high-risk populations and health care workers, if more than 4 months had passed since receipt of their third dose. The real-world effectiveness of the fourth dose against confirmed infection and severe illness remains unclear. In this study, we used data from the Israeli Ministry of Health national database to study the relative effectiveness of the fourth dose as compared with only three doses against confirmed infection and severe illness among older persons in the Israeli population.

Methods​

STUDY POPULATION​

For this analysis, we included persons who, on January 1, 2022, were 60 years of age or older and had received three doses of BNT162b2 at least 4 months before the end of the study period (March 2). We excluded the following persons from the analysis: those who had died before the beginning of the study period (January 10); those for whom no information regarding their age or sex was available; those who had had a confirmed SARS-CoV-2 infection before the beginning of the study, determined with the use of either a polymerase-chain-reaction (PCR) assay or a state-regulated rapid antigen test; those who had received a third dose before its approval for all older residents (i.e., before July 30, 2021); those who had been abroad for the entire study period (January 10 to March 2; persons were considered to be abroad 10 days before traveling until 10 days after their return to Israel); and those who had received a vaccine dose of a type other than BNT162b2.
For persons who met the inclusion criteria, we extracted information on March 4, 2022, regarding SARS-CoV-2 infection (confirmed either by state-regulated rapid antigen test or by PCR) and severe Covid-19 (defined with the use of the National Institutes of Health definition2 as a resting respiratory rate of >30 breaths per minute, an oxygen saturation of <94% while breathing ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <300) during the 14 days after confirmation of infection. During the study period, infections were overwhelmingly dominated by the omicron variant.3 We also extracted data regarding vaccination (dates and brands of first, second, third, and fourth doses) and demographic variables such as age, sex, and demographic group (general Jewish, Arab, or ultra-Orthodox Jewish), as determined by the person’s statistical area of residence (similar to a census block4).​

STUDY DESIGN​

The study period started on January 10, 2022, and ended on March 2, 2022, for confirmed infection and ended on February 18, 2022, for severe illness. The starting date was set to 7 days after the start of the vaccination campaign (January 3, 2022) so that at least the first four-dose group (days 8 to 14 after vaccination) would be represented throughout the study period (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The end dates were chosen to minimize the effects of missing outcome data due to delays in reporting PCR or antigen test results and to allow time for the development of severe illness.
The design of the study was similar to that of a previous study in which we assessed the protection conferred by the third vaccine dose as compared with the second dose.5 We calculated the total number of person-days at risk and the incidence of confirmed infection and of severe Covid-19 during the study period defined for each outcome. For persons who received the fourth dose, treatment groups were defined according to the number of weeks that had passed since receiving that dose, starting from the second week (8 to 14 days after vaccination). These four-dose groups were compared with two control groups. The first control group included persons who were eligible for a fourth dose but had not yet received it (three-dose group). Because persons who received the fourth dose might have differed from those who had not according to unmeasured confounding variables, a second control group was defined as persons who had received a fourth dose 3 to 7 days earlier (internal control group). This control group included the same persons as the four-dose groups, but during a period in which the fourth dose was not expected to affect the rate of confirmed infection or severe illness. The membership in these groups was dynamic, and participants contributed risk days to different study groups on different calendar days, depending on their vaccination status.​

OVERSIGHT​

The study was approved by the institutional review board of the Sheba Medical Center. All the authors contributed to the conceptualization of the study, critically reviewed the results, approved the final version of the manuscript, and made the decision to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data in this report. The Israeli Ministry of Health and Pfizer have a data-sharing agreement, but only the final results of this study were shared.​

STATISTICAL ANALYSIS​

Using quasi-Poisson regression, we estimated the rates of confirmed infection and severe Covid-19 per 100,000 person-days for each study group (included as factors in the model), with adjustment for the following demographic variables: age group (60 to 69 years, 70 to 79 years, or ≥80 years), sex, and demographic group (general Jewish, Arab, or ultra-Orthodox Jewish). Because incidences of both confirmed infection and severe illness increased rapidly during January 2022, the risk of exposure at the beginning of the study period was lower than at the end of the study period. Moreover, the fraction of the population in each study group changed throughout the study period (Fig. S1). Therefore, we included calendar date as an additional covariate to account for changing exposure risk.6 The end of the study period for severe Covid-19 was set to 14 days before the date of data retrieval (March 4), allowing at least 14 days of follow-up time for the development of severe illness. To ensure the same follow-up time for severe Covid-19 in all persons, we considered only cases of severe illness that developed within 14 days after confirmation of infection. The date used for counting events of severe Covid-19 was defined as the date of the test confirming the infection that subsequently led to the severe illness.
Persons who received four doses were assigned to groups according to the numbers of weeks that had passed since receipt of the fourth dose; for each outcome, we estimated the incidence rate in each of these four-dose groups and in the two control groups. We calculated two rate ratios for each treatment group and each outcome: first, the ratio of the rate in the three-dose group to that in each four-dose group; and second, the ratio of the rate in the internal control group to that in each four-dose group. Note that the higher this rate ratio is, the greater the protection conferred by the fourth dose of vaccine. In addition, adjusted rate differences per 100,000 person-days during the study period were estimated with a method similar to that used in our previous analysis.7 Confidence intervals were calculated by exponentiating the 95% confidence intervals for the regression coefficients, without adjustment for multiplicity. Thus, the confidence intervals should not be used to infer differences between study groups.
To check for possible biases, we performed several sensitivity analyses. First, we estimated the rate ratios for confirmed infection using an alternative statistical method that relied on matching (similar to that used by Dagan et al.8), as described in detail in the Supplementary Appendix; this approach could not be applied to the analysis of severe Covid-19 because of the small case numbers. Second, we examined the results of using data on infections confirmed only by PCR testing and excluding data on those confirmed by state-regulated antigen testing. Third, we repeated the analyses with data from the general Jewish population only. Fourth, we analyzed the data while accounting for the exposure risk over time in each person’s area of residence. Fifth, we analyzed the data while accounting for the time of vaccination since the third dose. Further details of the sensitivity analyses are provided in the Supplementary Appendix.​

Results​

STUDY POPULATION​

Figure 1.

Study Population.Table 1.

Demographic and Clinical Characteristics of the Persons in the Study Groups.
A total of 1,252,331 persons met the criteria for inclusion in the study (Figure 1). The total number of events and person-days at risk in each of the study groups, along with the distribution of covariates used in the analysis, are shown in Table 1, which provides statistics aggregated across weeks since receipt of the fourth dose from the second week onward. The information for each treatment group according to the week since receipt of the fourth dose is provided in Table S1. Overall, the distributions of covariates in the aggregated treatment groups are similar to those in the internal control group. As compared with the three-dose group, the aggregated four-dose groups and the internal control group included more person-days over the age of 80 years (24.9% and 25.1%, respectively, vs. 16.2%) and more person-days from the general Jewish population (94.2% and 93.7% vs. 84.4%). Those in the three-dose group had a larger number of risk days than did those in the aggregated four-dose groups (31.0 million person-days vs. 23.9 million person-days) but had more confirmed infections (111,780 vs. 42,325) and more severe cases (1210 vs. 355).​

PROTECTION CONFERRED BY THE FOURTH DOSE​

As shown in Table 1, the unadjusted rate of confirmed infection was 177 cases per 100,000 person-days in the aggregated four-dose groups, 361 cases per 100,000 person-days in the three-dose group, and 388 cases per 100,000 person-days in the internal control group. The unadjusted rate of severe Covid-19 was 1.5 cases per 100,000 person-days in the aggregated four-dose groups, 3.9 cases per 100,000 person-days in the three-dose group, and 4.2 cases per 100,000 person-days in the internal control group.
Table 2.

Results of the Quasi-Poisson Regression Analysis of Confirmed SARS-CoV-2 Infection.Table 3.

Results of the Quasi-Poisson Regression Analysis of Severe Covid-19.Figure 2.

Adjusted Rate Ratios for Confirmed Infection and Severe Illness.
The results of the quasi-Poisson regression analysis are summarized in Table 2 for confirmed infection and in Table 3 for severe illness. Figure 2 provides a graphical representation of the results for both confirmed infection and severe illness.
The adjusted rate of confirmed infection was lower in the four-dose groups than in the two control groups. The adjusted rate among persons in the fourth week (22 to 28 days) after receipt of the fourth dose was lower by a factor of 2.0 (95% confidence interval [CI], 1.9 to 2.1) than that in the three-dose group and was lower by a factor of 1.8 (95% CI, 1.7 to 1.9) than that in the internal control group. The adjusted rate of confirmed infection (after rounding) in the fourth week after the fourth dose was 171 cases per 100,000 person-days (95% CI, 165 to 177), as compared with 340 cases per 100,000 person-days (95% CI, 337 to 343) in the three-dose group and 308 cases per 100,000 person-days (95% CI, 299 to 317) in the internal control group (Table S2). In the analysis of adjusted rate differences, the group in the fourth week after the fourth dose had 170 fewer confirmed infections per 100,000 person-days (95% CI, 162 to 176) than the three-dose group, and 137 fewer confirmed infections per 100,000 person-days (95% CI, 125 to 14 than the internal control group. From the fifth week (29 to 35 days) onward, the rate ratio for confirmed infection started to decline. The adjusted rate of infection in the eighth week after the fourth dose was very similar to those in the control groups; the rate ratio for the three-dose group as compared with the four-dose group was 1.1 (95% CI, 1.0 to 1.2), and the rate ratio for the internal control group as compared with the four-dose group was only 1.0 (95% CI, 0.9 to 1.1).
The rate ratios comparing the control groups with the four-dose groups were larger and longer-lasting for severe Covid-19. For persons in the fourth week after receipt of the fourth dose, the adjusted rate of severe illness was lower by a factor of 3.5 (95% CI, 2.7 to 4.6) than that in the three-dose group and was lower by a factor of 2.3 (95% CI, 1.7 to 3.3) than that in the internal control group. The adjusted rate of severe Covid-19 (after rounding) in the fourth week after the fourth dose was 1.6 cases per 100,000 person-days (95% CI, 1.2 to 2.0), as compared with 5.5 cases per 100,000 person-days (95% CI, 5.2 to 5.9) in the three-dose group and 3.6 cases per 100,000 person-days (95% CI, 3.0 to 4.5) in the internal control group (Table S2). The adjusted rate differences were 3.9 fewer cases per 100,000 person-days (95% CI, 3.4 to 4.5) and 2.1 fewer cases per 100,000 person-days (95% CI, 1.4 to 3.0) than the three-dose group and the internal control group, respectively. Severe illness continued to occur at lower rates in the four-dose groups than in the control groups in later weeks after receipt of the fourth dose, and no signs of waning were evident by the sixth week after receipt of the fourth dose (Figure 2).​

SENSITIVITY ANALYSES​

The results of the matched analysis of confirmed infection were similar to the results obtained in the main analysis (Fig. S3). In addition, restricting the quasi-Poisson regression analysis to the general Jewish population, adding as a covariate the exposure risk over time in each individual’s area of residence, or adding as a covariate the time since administration of the third dose did not substantially change the results of the main analysis (Figs. S4 and S5).
As described in the Supplementary Appendix, the testing policy in Israel was changed in early January 2022 (before the study period) for persons younger than 60 years of age. Even though the testing policy for the study population (persons ≥60 years of age) did not change, we tested the possible effect of the type of diagnostic test used to confirm infection by repeating the analysis counting only infections confirmed by positive PCR tests. This resulted in only very minor changes to the estimated level of protection conferred by the fourth dose (Figs. S4 and S5). In addition, we compared the testing rate and test type (PCR or antigen) among persons who received the fourth dose as compared with those who received only three doses and found the differences to be of limited extent (Fig. S2).​

Discussion
The omicron variant is genetically divergent from the ancestral SARS-CoV-2 strain for which the BNT162b2 vaccine was tailored. The results presented here indicate that as compared with three vaccine doses given at least 4 months earlier, a fourth dose provides added short-term protection against confirmed infections and severe illness caused by the omicron variant. The incidence rate for confirmed infection was lower by a factor of 2 and the rate of severe disease lower by a factor of 3 among persons in the fourth week after receiving the fourth dose than among eligible persons who did not receive the fourth dose.
Comparing the rate ratio over time since the fourth dose (Figure 2) suggests that the protection against confirmed infection with the omicron variant reaches a maximum in the fourth week after vaccination, after which the rate ratio decreases to approximately 1.1 by the eighth week; these findings suggest that protection against confirmed infection wanes quickly. In contrast, protection against severe illness did not appear to decrease by the sixth week after receipt of the fourth dose. More follow-up is needed in order to evaluate the protection of the fourth dose against severe illness over longer periods.
Although our analysis attempts to address biases such as confounding, some sources of bias may not have been measured or adequately controlled for — for example, behavioral differences between persons who received the fourth dose and those who did not. For severe illness, differences in the prevalence of coexisting conditions could potentially have affected the results; however, this information is not recorded in the national database, and therefore we did not adjust for such differences. Differences in coexisting conditions could also be associated with differential treatment with antiviral drugs such as ritonavir-boosted nirmatrelvir, which could have affected the results. To address some of these biases, we compared the rate of confirmed infection and severe illness within the group of people who received the fourth dose. Estimates of the rate ratio during the first days after vaccination could include the effect of transient biases (Fig. S6). These potential biases include the “healthy vaccinee” bias,9 in which people who feel ill tend not to get vaccinated in the following days, which leads to a lower number of confirmed infections and severe disease in the four-dose group during the first days after vaccination. Moreover, one would expect that detection bias due to behavioral changes, such as the tendency to perform fewer tests after vaccination, is more pronounced shortly after receipt of the dose.
Thus, we compared the rates of confirmed infections and severe illness at different weeks after the fourth dose, from the second week onward, with the rates on days 3 to 7 after its receipt, a period during which the transient biases would have diminished but before the vaccine would be expected to have affected the rate of the outcomes of interest.6 The rate ratios obtained for confirmed infections were very similar to those obtained when comparing the treatment groups with the persons who did not receive a fourth dose. For severe illness, the rate ratios relative to the internal control group were lower than the rate ratios relative to the three-dose group. Even when the internal control group was the basis for comparison, the rate ratios for severe illness were still higher than those for confirmed infection and did not show signs of waning immunity.
In addition, several sensitivity analyses were performed to assess the robustness of the results to further potential biases. First, we performed the analyses using data only from the general Jewish population, since the participants in that group are more common in the population that received the fourth dose. Second, we included in the model the risk of exposure in the person’s area of residence. The results of these analyses were similar to the results of the main analysis.
Overall, these analyses provided evidence for the effectiveness of a fourth vaccine dose against severe illness caused by the omicron variant, as compared with a third dose administered more than 4 months earlier. For confirmed infection, a fourth dose appeared to provide only short-term protection and a modest absolute benefit. Several reports have indicated that the protection against hospital admission conferred by a third dose given more than 3 months earlier is substantially lower against the omicron variant than the protection of a fresh third dose against hospital admission for illness caused by the B.1.617.2 (delta) variant.1,10,11 In our study, a fourth dose appeared to increase the protection against severe illness relative to three doses that were administered more than 4 months earlier.​

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Mr. Bar-On, Dr. Goldberg, and Dr. Mandel and Drs. Huppert and Milo contributed equally to this article.
This article was published on April 5, 2022, at NEJM.org.
"

 

[missy]

"

Why do vaccines wear off so quickly?​

In this week's edition of the Covid Q&A, we look at the waning effectiveness of vaccines. In hopes of making this very confusing time just a little less so, each week Bloomberg Prognosis picks one reader question and puts it to experts in the field. This week’s question comes to us from Ruth in Chicago. She asks: I keep wondering why the Covid vaccine’s effectiveness wanes so quickly. Is it the messenger RNA technology? Something else? The reality of life after vaccination has looked a little different than we imagined. There was that glorious period after vaccines first rolled out when it seemed like the pandemic was at long last over and we could just slip right back into our old pre-Covid lives. SARS-CoV-2, though, is a wily virus. It keeps evolving around our defenses, with new variants like omicron rendering vaccines and treatments less effective. “The situation with the Covid-19 vaccines actually is similar to the situation that we have annually with the flu vaccine,” says Katrine Wallace, an epidemiologist at University of Illinois at Chicago. It’s not that the effectiveness of the shots is wearing off so much as the virus is evolving to be better at evading the first-line defenses of vaccines. “The available vaccines were created for the original 2019 ‘wild-type’ SARS-CoV-2 virus,” says Wallace. “The virus has undergone multiple mutations since then, and several new variants have circulated globally (alpha, beta, delta, omicron). Viruses mutate all the time, and a viral variant occurs when a mutation causes the virus to behave differently, either to become more transmissible, cause more severe disease or cause decreased effectiveness of available vaccines or medications.” "

 

[Karl_K]

tue afternoon im getting my second booster I decided to stick with Pfizer again

 

[LilAlex]

This is the first one that I am not 100% sure what/when to do. The additional protection seems short-lived -- although I guess the whole story has not been written for severe illness which is pretty much all that matters.

I ran to get the first pair and the booster the minute they were available at work. The second booster is "on my to-do list" for this coming week, but I have a little less confidence. No fears or concerns; just a little less elated about the prospect.

 

[Gloria27]

Hubby tested pozitive just now, he's been having simptoms since yesterday when he tested negative. Wonder if I gave it to him (asymptomatic) or I'm about to get it from him.

We are hermits with almost zero social life but he did go work for 2 days last week.
Will defo order stuff online and keep away from other people for a while.

 

[missy]

Hubby tested pozitive just now, he's been having simptoms since yesterday when he tested negative. Wonder if I gave it to him (asymptomatic) or I'm about to get it from him.

We are hermits with almost zero social life but he did go work for 2 days last week.
Will defo order stuff online and keep away from other people for a while.

Hope he recovers soon Gloria and that you remain well.

This is the first one that I am not 100% sure what/when to do. The additional protection seems short-lived -- although I guess the whole story has not been written for severe illness which is pretty much all that matters.

I ran to get the first pair and the booster the minute they were available at work. The second booster is "on my to-do list" for this coming week, but I have a little less confidence. No fears or concerns; just a little less elated about the prospect.

I feel the same way. We got the first three as soon as we could. But now I am not excited about the second booster just because it is short lived. I do not really want to get two more boosters this year and am hoping one will be sufficient. So I am pondering what is the best course of action at this time. I don't think anyone can say for sure. Good luck with your second booster Alex.

 

[Gloria27]

Thanks, Missy!

 

[missy]

"

Is another surge already underway?​

More than 50 people who attended an annual dinner for Washington A-listers in early April have since tested positive for Covid-19, as an outbreak among the political elite — including D.C. Mayor Muriel Bowser and Speaker of the House Nancy Pelosi — has made its way through the capital. But the most recent spate of high-profile cases isn’t isolated to Capitol Hill. New York City’s Mayor Eric Adams announced Sunday that he, too, has Covid. Recently, as Covid-positive friends cancel dinner plans and co-workers call in sick, it has sometimes felt like the low official case numbers we’re now seeing are, well, maybe a bit too low. Testing across the U.S. has scaled back significantly, raising the question of whether Covid is spreading more than we realize. Demand for lab-based testing has gone down since omicron’s peak in January and following the end of government-subsidized testing. Now, more people are relying on at-home testing, if they choose to test at all. That means positive results are rarely being reported. “There’s always more spread than we can detect,” says Abraar Karan, an infectious disease physician at Stanford University. “That’s true even more so now than earlier in the pandemic.” Experts worry that a disregard for case surveillance and a shift in federal funding priorities will leave the U.S. vulnerable to another surge. In fact, another surge could be happening right now without us realizing it. (Read the full story here.) Speaker of the House Nancy Pelosi is among the Washington elite who have recently tested positive. Photographer: Al Drago/Bloomberg “We are probably underestimating the number of infections we are having now because many of the infections are either without symptoms or minimally symptomatic and you will miss people that do it at home,” Anthony Fauci, the top medical adviser to President Joe Biden, told Bloomberg TV last week. Though omicron has proved to be more mild than past strains, during its peak it caused a record-breaking number of hospitalizations — including among kids. The Centers for Disease Control and Prevention’s new risk metrics rely less on case counts and more on hospitalizations and ICU capacity, which are considered lagging indicators of how the virus is spreading. So by the time another surge rolls around, the time to intervene may have already passed. There’s concern among public health experts that past pandemics could hold a warning for how we’re now handling Covid. After cases started to go down following the first two waves of the 1918 influenza outbreak, public sentiment shifted and many health measures were lifted. But in 1919, at the tail end of the pandemic, a fourth wave hit New York City, causing deaths to spike higher than they had during prior waves, according to a government-funded study. “These late waves of the pandemics are sometimes the deadliest because people have given up,” says Gregg Gonsalves, associate professor of epidemiology at the Yale School of Public Health. — Madison Muller "

 

[Karl_K]

tue afternoon im getting my second booster I decided to stick with Pfizer again

2nd booster is kicking my fanny.
Arm sore, headache, cold/hot flashes and no energy.

Easter plans with family all canceled because my niece who is a nurse working in a nursing home tested positive for covid for the 3rd time. No symptoms.
Positive on on the rapid test and pcr I believe.
They had a patient transfer in who tested positive on day 2 and a bunch of the staff tested positive on that weeks testing a few days later.
She had her first booster but not the second yet as well as having covid 2x before.

 

[missy]

2nd booster is kicking my fanny.
Arm sore, headache, cold/hot flashes and no energy.

Easter plans with family all canceled because my niece who is a nurse working in a nursing home tested positive for covid for the 3rd time. No symptoms.
Positive on on the rapid test and pcr I believe.
They had a patient transfer in who tested positive on day 2 and a bunch of the staff tested positive on that weeks testing a few days later.
She had her first booster but not the second yet as well as having covid 2x before.

Feel better Karl! And good for you for being proactive. I am sorry about the holiday plans being canceled but it is 100% the best thing to do. This way you know there will be future holidays you can all celebrate together. Ensuring your good health today allows for a tomorrow full of happy celebrations. I hope your niece recovers fully.

 

[Gloria27]

Hope he recovers soon Gloria and that you remain well.

No such luck, I got it.
It's not that bad but the body aches are...unpleasant...ugh....
Otherwise I'm on normal energy levels and can do chores and stuff.

Guess I'll survive altough if this were another variant, I'd probably be a bit worried.

 

[LightBright]

Multiple people in my family and extended family have cold symptoms (all adults vac, nearly all boosted). I was told I had to be in person to the DMV last week and less than 10% of the crowded room were wearing masks (me in N95). I was there for 2.5 hours, only one door open to the outside. All DMV employees wearing masks and behind plexiglass booths. So it’s “back to normal” (I was pretty surprised) in my area but I think that will surely increase cases. The family members with cold symptoms all tested neg on the RAT, we will test one of us in each family with PCR today.

 

[LightBright]

We invested in N95s for the family, and we don’t do anything social including answering the door without N95.

But I do hike and take walks in public gardens and I’m wondering if I need to step up my game. Some people seem to be wearing masks even outside now! Does anyone have advice on masking outdoors (in places where you would walk by other people)?

 

[Gloria27]

Multiple people in my family and extended family have cold symptoms (all adults vac, nearly all boosted). I was told I had to be in person to the DMV last week and less than 10% of the crowded room were wearing masks (me in N95). I was there for 2.5 hours, only one door open to the outside. All DMV employees wearing masks and behind plexiglass booths. So it’s “back to normal” (I was pretty surprised) in my area but I think that will surely increase cases. The family members with cold symptoms all tested neg on the RAT, we will test one of us in each family with PCR today.

A family member that is double vaxxed and had symptoms tested negative multiple times and then his GF tested pozitive (LFT test). Obviously he had it.
Not saying everyone testing negative (with cold symptoms) has it, but I think it is possible.