Paper and Threads

Decisions about a 3rd mRNA vaccine became even more complicated this week.  What is the US trying to achieve with vaccines?  What clinical trial data is available that supports the need of a 3rd dose?  Who should get 3rd doses and when?  What is our obligation to other countries?

1.  Is there enough data to demonstrate that we need it?  Not yet.  The recent information from Israel is not yet published or presented fully.  The breakthrough cases and results from other studies from August will be analyzed for more information with both mRNA vaccines (Israel uses Pfizer).  There are different opinions about the necessity from very good scientists.  And almost always the US "waits for the science" before making a recommendation.

2.  It is estimated that there are a million people who already made a decision and got their 3rd dose, and no data has been collected re: efficacy and safety in a standardized way. 

3.  Pfizer already submitted their proposal to give a third dose.  Today it was reported that Moderna applied to give a 3rd dose, but the amount in the dose is slightly different than their first and second shots.  That may delay their data review and slow their FDA and CDC approval. 

4.  Third doses were approved by both the CDC and FDA for patients with immune deficiency and they are currently being administered. The 3rd dose of the vaccine for the general public needs to be approved by them too.  The FDA VRBPAC meeting is scheduled for September 17th.  The CDC ACIP meeting is not yet on their schedule.  See Below

Other information: 

Israel:  "Israeli officials say their data shows that the potency of Pfizer's vaccine wanes over time against severe disease and hospitalization, but that a third shot bolsters protection significantly.  The FDA wants to see the raw data, to make sure it backs up summaries that the Israeli government has provided."  NYT Sept 3,2021 

Sharing our vaccines with the world:  130 million doses have already been shipped to 90 countries. And 200 million more doses will be shipped before the end of 2021 and another 300 million doses before July 2022.  This is data presented by Dr. Fauci at this week's White House Briefing.  There are also plans for the US to develop and fund more vaccine manufacturing.

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I spent all of Monday watching the meeting of the CDC Advisory Committee on Immunization and Practices (ACIP).  Most of the day the data submitted for the Pfizer BLA was reviewed very carefully and then the independent experts on the committee voted 14 to 0 and approved the BLA.  From 4-5PM the working group for "3rd shots" discussed a framework for their analysis of and planning for additional doses of the mRNA vaccines and presented recent data from 5 US studies of vaccine efficacy and breakthrough cases.

While there is some waning vaccine efficacy in older people against asymptomatic and mild-moderate Covid infections, vaccine efficacy is still high against severe infections, hospitalizations and deaths.  The working group plans to meet again in mid-September to review new data from the analysis of infections in August when the delta variant took over the other Covid variants in the US.  See Below

Some vaccines require annual "boosters" against mutations (influenza) and other vaccines require a sequence of 3 doses to establish long term immunity  (hepatitis B and human papilloma virus).  Studies performed after a 3rd dose may clarify the best way to establish strong immune responses to SARS-CoV-2.   Immunocompromised patients are currently receiving a 3rd dose, and the next group to be considered may be health care workers, long term care facility patients, and people older than 65.  Both the FDA and CDC will have to carefully consider the data and approve the final plan for more shots.  Stay tuned, and wait for more information in September. 

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This is an interesting compilation of data from NY between May 3 and July 25, 2021.  It illustrates the type of information that would be helpful in all of the states in order to determine whether and when we might need booster shots.  This full paper was published in MMWR by the CDC this week and I wanted to briefly review the results.  People >60 years were eligible for vaccination by Mar 10 and to all residents >18 years by April 6. 

Breakthrough infections and hospitalizations were counted in fully vaccinated (10,135,322) and unvaccinated (3,472,197) people and results were stratified in 3 ages groups (18-49), (50-64), and (>65).   Vaccines received were Pfizer 51.3%, Moderna 39.8% and J and J 8.9%.  During this period the vaccination rate increased to 65% as the delta variant increased from <2% to >80%.   See Below 

Results: 

Cases:  9,675 in vaccinated and 38,505 in unvaccinated (1.31 vs 10.69/100,000 person days). Case rates were generally similar across all age groups in both vaccinated and unvaccinated subjects.  Cases decreased from March through the end of June and then increased with the delta surge through July for both vaccinated and unvaccinated. Vaccine efficacy for all age groups generally declined from 91.7% to 79.8%.

Hospitalizations:  1,271 hospitalizations among vaccinated and 7308 among unvaccinated.  They declined from March to June, and then increased in July as the delta variant became predominant.  There were more hospitalizations in the 65+ group than in the other two younger cohorts, but no information about comorbidities was available.  Vaccine efficacy against hospitalizations remained above 90% in all age groups.    And finally the ratio of hospitalizations was moderately lower in the vaccinated group (13.1 per 100 cases vs 19.0).

These types of real world studies are difficult to analyze fully but they may be equally or more important in defining objectives, i.e. prevention of disease and hospitalizations by vaccinations.    

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As my son Jason wrote on Instagram on Monday "I've said here many times that these vaccines are the most studied medical interventions in human history, building on over 20 years of brilliant research to deliver a miracle in one of humanity's greatest moments of need.  The FDA's full approval now validates the safety and effectiveness of Pfizer's shot, and a Moderna approval is likely only a few weeks away."  Now we can only hope that those who didn't take the vaccine because they wanted full FDA approval will get vaccinated so our country can control this pandemic.  As the virologists say, the virus will not stop spreading until there are no more susceptible people.  The vaccine was fully approved for two doses 3 weeks apart for people aged 16 and older.

Almost 100 million people in the US, ages 12-95+, have received the Pfizer vaccine and efficacy and safety was proven over and over.  But the FDA's new full approval for people age 16 and older was based on tens of thousands of data pages on the 44,000 volunteers in the Phase 3 Clinical Trial.  These trial subjects will still all be followed for a full 24 months from enrollment, so we should continue to see more scientific data until the trial ends.   Vaccine efficacy which was 95% when the EUA was granted has dropped slightly to 91% and there were no new safety concerns. Were any of the new cases due to the delta variant?  I couldn't find that info.  Children age 12-15 are now being vaccinated under the emergency approval until the FDA-CDC complete their review of the data in these adolescents. 

See Below 

The Pfizer vaccine was approved for an EUA (Emergency Use Authorization) in December 2020 and has been granted a BLA (Biologic License Application) this week.  There are some new changes, for example the vaccine now has a name that no one will remember, it can be advertised and sold, and physicians may be able to use it "off-label" which means some variation from the current schedule of 2 doses 3 weeks apart.  Importantly it is still free for all of us in the US. It is important to remember that this dosing was determined in a carefully monitored study.  Consumers should beware of use in a new regimen without equally good scientific information proving vaccine efficacy and safety.  Children <12 years old should not receive the current dose, off-label, because the trial to establish the correct, SAFE dose has not yet been determined.

Now that the vaccine has full approval by the FDA  many institutions, companies and organizations have mandated vaccination for employment - including the active-duty Military, and many schools, universities, and hospitals.  85 million Americans are still unvaccinated and mandates like these will make it safer for all of us.  New cases are up to 150,000 per day in this surge and it is nearly impossible to calculate your risk of infection, especially in states without mandates for vaccinations and masks.  Come on people - it will take everyone to be vaccinated to change the course of this pandemic and get us back to our previous lives.

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Yesterday 2 of my unvaccinated grandsons asked if they could come over to watch me make 3 layer cloth masks for them before school starts.  One of them likes the elastic to go around his neck and head like N95 masks so I am his provider!  For this blog post I am reposting a Covid collage that appeared on July 11, 2020.  In that blog post I described the 3 phases of the clinical trials for the mRNA vaccines that were beginning http://www.paperandthreads.com/2020/07/roll_up_your_sleeve.php.  I now have created 122 Blog Posts about Covid and I feel as if we are back at the beginning. 

It is possible to collect plasma from patients infected with the delta variant to measure "neutralizing antibodies" to determine vaccine efficacy.  But following breakthrough cases in the real world gives scientists information about the full immune response in vaccinated patients.  The CDC follows these very carefully and the increase in the number of breakthrough cases in vaccinated people made them decide that it would be better to stay ahead of the virus.    High rates of infection in the unvaccinated leads to more mutations!Continue below. 

Dr. Fauci, in the CDC announcement last Wed, presented 4 reasons for considering booster shots 8 months after our second doses:

1.  Antibody levels decrease over time.  2.  Higher antibody levels are more protective.  3. Higher antibody levels may be required against the delta variant.  4.  There is a 10-fold increase in antibody levels against delta variants after a 3rd dose of the same vaccine.  There are many vaccines that require several doses and/or annual boosters, so this is not an indication of vaccine failure.  It is still enormously effective against hospitalizations and deaths due to delta variant, less so against mild to moderate disease, thus the new recommendation.  Schedule your booster shot at one 0f 80,000 centers 8 months after you received your 2nd dose of mRNA vaccine.  Please don't rush out before that!  Two of our closest friends (same age as us) both developed Covid recently and they were so thankful for the vaccine, because the infection was just like a cold.     

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