August 23, 2021 Weekly Briefing

August 23, 2021, Weekly C19 Briefing Summary: Vaccination induced immunity is durable if the endpoing is severe disease but not if the endpiont is infections; boosters work to increase protection against infections; therefore, boosters are needed if we are to stop the current wave without returning to lockdowns; a new drug from Israel looks promising in small, Phase II clinical trials and another antibody cocktail from AstraZeneca administered IM gets excellent results in early Phase III trials; do breakthrough infections cause long-covid?–preliminary data point to yes:  it is time to update primary vaccination regimens to consider heterologous dosing with a longer inter-dose interval; and lastly, mainly for the providers, the case for boosters against Delta and why we don't need new vaccines yet, just another shot of the great ones that we currently have.  

949.  Protection from infection among vaccinated dropped from 92% in May to 80% by the end of July. 
https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e1.htm?s_cid=mm7034e1_w

950.  Among nursing home residents, protection against infection declined from 75% (March through May) to 53% in June and July.  
https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e3.htm?s_cid=mm7034e3_w

951.  An analysis of data from 21 hospitals in 18 states shows continued protection against hospitalization (86% overall and 90% among those with immunocompetency) from vaccination. 
https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e2.htm?s_cid=mm7034e2_w

952.  New large observational study data from Israel shows Pfizer to be 86% effective at preventing infection among those 60 and over at one week or more after a booster (up from 30% before the booster).  Currently, Isreal is giving boosters to all people over 50 and is now preparing to give them to everyone over 40 by September 6.  According to the study leader, it is now clear that, with regard to Delta, "The triple dose is the solution to curbing the current outbreak." 
https://www.jpost.com/health-science/pfizer-covid-vaccine-86-percent-effective-after-third-shot-maccabi-677053

***953.  New Israeli C19 drug flies through small Phase II trials and is >90% effective at reversing severe C19 disease in 5 days or less.  CD24 is a naturally occurring molecule that downregulates just the immune process that leads to the cytokine storm without affecting other aspects of immune function.  This gives it significant advantages over, say, dexamethasone, which broadly suppresses immunity and has significant side effects.  EXO-CD24 also uses a new delivery system technology that employs an exosome to get the molecule just to the target cells without affecting any other cell; no side effects have been reported thus far.  
https://healthcaremarketexperts.com/en/news/israels-promising-covid-drug-successfully-passes-ii-phase-of-research/

954.  AstraZeneca announces their 2 mAb cocktail which is administered IM reduced the risk of developing symptomatic C19 by 77% versus placebo.  There were no cases of severe disease or death in the intervention group compared to 3 hospitalizations and 2 deaths in the placebo group.  There were no significant AEs and, importantly, 75% of the trial population had comorbidities, including immunocompromised.  AZD7442 was derived from the B cells of convalescent patients. PROVENT was a phase III randomized trial conducted at 87 sites in the U.S., U.K., Spain, France, and Belgium. Participants were adults "who would benefit from prevention" with the long-acting antibody, were unvaccinated at the time of enrollment, and were negative for SARS-CoV-2 via serology testing.  Overall, 5,200 were randomized 2:1 to receive the drug or placebo.
https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/azd7442-prophylaxis-trial-met-primary-endpoint.html

955.  In a study of 1,500 healthcare workers, 19% of breakthrough cases developed long-covid with chronic symptoms > 6 weeks post-infection, despite mild or asymptomatic primary infections.  These are the first data to help answer the key question of the pandemic at this moment: Should we be doing everything we can to avoid infections, including employing boosters, or should we just focus on protecting people from severe disease (in which case it looks like we don't actually need boosters yet)?  You all know what I think:  It is wiser to err on the side of safety.  Until the issues of whether or not mild breakthrough infections can progress to chronic disease and/or cause permanent injury to brain, pulmonary, vascular, and other organ tissues that could hasten disease later in life, we should take all reasonable precautions, including boosters, to prevent getting infected.  When the CDC made the decision to only follow and investigate breakthrough cases that led to severe disease, they made a wrong turn on our journey out of the pandemic; now we must wait for other countries to provide the data needed to settle critical issues such as this one.  
https://www.nejm.org/doi/full/10.1056/NEJMoa2109072

956.  In the largest study of symptoms in the long-covid population to date, an international online survey study of 3,800 patients with long-covid finds the probability of ongoing symptoms at >6 months post-infection to be 92%.  Fatigue, post-exertional fatigue/malaise, cognitive difficulties, headaches/muscle aches, and other neuropsychiatric issues were the most common symptoms.  Relapsing/remitting courses were common. Especially of note were symptoms not yet commonly associated with C19, including increased sensitivity to medicines, the onset of new allergies, seizures, increased suicide, and facial paralysis at rates that outpace that which is expected in the general population. Several of these symptoms overlap with symptoms of Mast Cell Activation Syndrome.  Dysautonomia, including Postural Orthostatic Tachycardia Syndrome (POTS), and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) appear to be of particularly high risk for this population who experience significant worsening of symptoms after physical or mental exertion.  Memory and cognitive dysfunction were experienced by over 88% and were equally common across all ages.  What will be the long-term impact of long-covid on work, daily life, and mortality?  Memory and cognitive dysfunction, together with other commonly reported neuropsychiatric symptoms track with prior data showing consistent brain injury (loss of gray matter) following even mild or asymptomatic infections on MRI when compared against pre-infection brain scans.  
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00299-6/fulltext

957.  Heterologous vaccination boosters work significantly better (much higher neutralizing antibody titers) than homologous among those who received the Oxford/AstraZeneca vaccine.  This strengthens the signal from the data showing that vaccines from different platforms or using different vectors confer more robust immunity compared to two or three shots of the same vaccine.  
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01891-2/fulltext

958.  In addition to heterologous vaccination regimens, spacing out the time between doses can also likely improve immunogenicity.  Pfizer recently reported 8 weeks to be the ideal time between doses (see prior briefing).  The authors of this paper recommend extending the time between doses to at least 7 weeks for persons over 80 who are assumed to be less immunoreactive.  Are the data showing Moderna to induce more durable protective immunity against infections compared to Pfizer the result of Moderna's higher dose?  Unlikely since subsequent data have shown that even a quarter-dose of Moderna provokes a comparable immune response to a full dose.  Is it because Moderna and Pfizer use different lipid nanoparticle envelopes to gain entry into cells?  Also unlikely since there is neither evidence nor a plausible theoretical mechanism for lipid nanoparticles playing any role in the immune response.  The most likely reason Moderna is holding up better than Pfizer is that the interdose interval was 25% longer (4 weeks for Moderna compared to 3 weeks for Pfizer).  
https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(21)00205-1/fulltext
 
Why Delta is so successful and why an additional dose of the current vaccines (boosters) offers us the best protection (959 - 963)

I. Transmissibility: Delta, as we know, spreads faster, is probably a little more virulent, and, perhaps most importantly, has resulted in much higher rates of breakthrough infection compared to any of the prior VOCs.  The mutations that define Delta have enhanced its fitness (its ability to get its genes into the future) significantly.  Containing certain key mutations seen in other VOCs, Delta is associated with a much higher viral replication rate, which in turn has led to a shorter average incubation period (3-4 days vs. 6-7 days), and dramatically higher viral titers (about 1,200 times higher than the viral titers associated with the ancestral 'wild-type' strain).  Together, these evolutionary changes have made Delta much more transmissible and it is most likely its enhanced transmissibility that has enabled Delta to outcompete other VOCs, including Alpha (the UK variant).  

II. Immune evasion: Delta also contains some mutations that have enabled it to evade a few specific neutralizing antibodies.  However, as we can see from the following antigen cartology graphic, Delta has actually migrated genetically away from the ancestral 'wild type' strain (and therefore, away from vaccine-induced immunity since the vaccines were tuned to that strain) significantly less than most of the other VOCs.  In fact, is it notable that the two variants that migrated least in the direction of immune escape are Alpha and Delta–the two VOCs that have been most successful in the US and around the world.

III. Immunoprevalence: So far, mutations that increase transmissibility are being evolutionarily favored over mutations that increase immune evasion.  Why?  It could be that we simply have not yet seen sufficient immune evasion to enable any strain, even Beta (the South African VOC), to truly bypass prior immunity well.  However, so long as there is a large reservoir of immune naive people among which to spread, competition between variants is likely to favor the swift over the crafty.  

Unvaccinated people tend to cluster in families and communities and this is reflected in the current wave of spread.  As more people get infected and vaccinated, however, that will likely change.  As the virus encounters more and more people with prior immunity, it will be harder for it to rip through a population.  Most recently immunized people have enough protection to repel infection (see IV below) and as populations approach herd immunity, the speedy transmission associated with Delta will likely become less of a fitness advantage.  Eventually, only strains that can bypass prior immune protection will be able to carry Scov2's genes into the future (cause infections) and the pandemic race, on the viral side of things, will shift from favoring the swift to the crafty VOCs with the greatest degree of immune escape.  

IV.  Current breakthrough infections are a numbers game: With so many people unvaccinated, the pandemic is still in the early sprint portion of the race that favors the swift.  We believe (but it is not settled science) that transmissibility is directly informed by viral titers.  It is assumed that higher viral titers means also more viral shedding and that more viral shedding means the production of more viral aerosols (the chief route of transmission of C19).  Delta, the most transmissible variant thus far, has the highest viral titers.  It also has the shortest incubation time which further increases the rate of transmission as persons infected with Delta can spread the virus 3 days sooner after exposure compared to those infected with prior VOCs, advancing the forward chain of transmission at a faster clip.  Higher viral shedding giving rise to the exhalation of higher titers of viral aerosols means more virions are being inhaled to colonize the nose and throat.  

Vaccination builds high levels of neutralizing antibodies (higher even than natural infection) including IgA in the MALT.  This protective regiment of immune foot soldiers patrols mucosal tissues looking for Scov2.  Their job is to prevent colonization or halt it before it can progress to infection by quickly shutting down the virus while it is still in mucosal epithelial cells or swimming in the fluid that bathes those cells.  Higher numbers of viral invaders require higher numbers of neutralizing IgA.  And neutralizing antibody titers are at their highest soon after vaccination (or infection).  But antibody titers following the standard one or two-dose vaccination regimen have been shown to wane over time.  And as antibody titers wane, so does our ability to repel the virus before it has a chance to colonize or progress from colonization to infection–especially with Delta and the bigger army of viral invaders it produces.  

V. Booster shots increase the number of troops in our defensive regiments, including the one in the MALT:  Booster shots have been shown to very quickly increase antibody titers dramatically.  Earlier this month, Novavax released data showing that a booster shot of their vaccine increased neutralizing antibody titers four-fold compared with the peak antibody titers seen soon after the standard one or two-dose regimen of primary vaccination.  Moderna has released similar data with respect to its vaccine when given as a booster.  

Boosters not only dramatically increase the circulating level of neutralizing IgA in the MALT, but they also cause antibody-making B cells to multiply–and remain as memory B cells.  The increased pool of memory B cells left behind after a booster shot will enable a faster, stronger antibody response to subsequent exposures. Boosters also promote a process called affinity maturation, in which ‘engaged’ B cells (B cells that have been triggered by the vaccine) travel to the lymph nodes where they themselves begin to mutate to try to predict viral mutation, making the antibodies they produce more likely to have the ability to neutralize a future virus.  Titers of memory B cells and antibodies will eventually plateau with repeated boosting (or reinfection), but it is unlikely that such levels have been reached in people who have had the standard primary regimen of any of the C19 vaccines.  A third exposure to the spike protein will also likely alert the immune system to keep antibody titers higher for longer as discussed last week.   

VI. Summary:  The current wave of infections and higher rate of breakthrough infections is probably best attributable to the specific combination of mutations that have endowed Delta with the ability to replicate extremely quickly to cause extremely high viral titers, and not a result of its immune-evasion capability.  This is why we need boosters but don't yet need a new vaccine tuned to new variants.  Higher viral titers likely mean higher viral shedding and therefore, higher titers of viral aerosols emitted by those who get infected.  Higher titers of viral aerosols during an exposure means more viral invaders getting in to colonize the nose and throat.  The best defense against a high initial infectious dose is to have the highest possible titers of neutralizing antibodies circulating in the MALT.  

This week we have the first strong signal from the vetted scientific literature showing that even mild breakthrough infections can cause chronic symptoms of long-covid.  Can breakthrough infections also cause the same gray matter destruction we saw demonstrated by MRI among unvaccinated persons who experienced mild or asymptomatic C19?  While we don't have that data yet, all indications point to yes.  If we care about this and not just the hospitalization rate, then the time for boosters is now.  

The Biden Administration, on advice from the CDC, is pushing for expanding boosters to all vaccinated persons at 8 months post-primary vaccination regimen, to begin on Sept. 20.  As has been the case throughout the pandemic, these recommendations from the CDC lag significantly behind the data.  We already know, for example, that at 6 months post-vaccination with Pfizer or Janssen, protection against infection is probably less than 50%.  What will it be at 8 months and why (for god's sake!) should we wait to find that out?  

An evidence-based approach to offering boosters would dictate a staggered schedule specific to each vaccine that might look something like: 4 months post-primary vaccination with Pfizer or Janssen; 6 months with Moderna.  It would also dictate that the Janssen regimen be increased to two doses and that all the vaccine regimens be changed to lengthen the interdose interval to about 8 weeks.  This would be following the science as it emerges in real-time and that is what a successful pandemic response calls for.  

Once the vaccines are certified by the FDA (Pfizer is expected to receive certification this week), it will be up to physicians to make their own decisions about whether, which, and when to give them as boosters.  My take: our office of experienced providers should consider the merits of an evidence-based approach that looks more like the Israeli strategy and not simply follow the recommendations of the CDC, whose sense-makers are still mired in viewing Scov2 through the lens of prior, better-understood viruses.  Scov2 is not like influenza and keeping people out of hospitals is not medically, ethically, or from a cost perspective (with respect to healthcare for chronic conditions and the effects of those conditions on learning and work productivity) a reasonable endpoint of protection against C19.