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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.
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C19 Weekly Briefing Supplement on the importance of maintaining high circulating levels of neutralizing antibodies through vaccine boosters.
Booster Shots The new wave of the pandemic is being driven by Delta which bypasses prior immunity at a higher rate than any previous variant. How is Delta managing to do this? It appears likely that some combination of mutations allow it to escape key neutralizing antibodies while affording it the ability to generate more viral copies (viral titers among people infected with Delta are 1,000 times higher than those of people infected with the original strain of the virus), combined with timing. People have the highest level of neutralizing antibodies shortly after getting vaccinated or infected and then those levels wane gradually over months until they are low enough to allow for breakthrough infections. It is likely that those who were vaccinated or infected several months ago have less immune protection against getting infected than those who were vaccinated or got infected more recently. The process of getting C19 starts with exposure–a person inhales viral aerosols that stick to mucous membranes in the nose, nasopharynx, or lungs. This is called colonization. If someone has high levels of circulating neutralizing antibodies in the immune system of the mucous membranes (called the "MALT"), they can kill off the virus before it penetrates into the body's interior to cause an infection. This is what happens in most people who were recently vaccinated. However, as circulating neutralizing antibody titers wane over time, the MALT has fewer soldiers to keep colonization contained and this allows breakthrough infections to occur. There are now sufficiently ample data showing that an additional shot of vaccine boosts circulating neutralizing antibodies to levels much higher than those seen after completion of the initial vaccination regimen. This should provide those who get booster shots with much stronger protection against getting infected (lots of neutralizing antibodies circulating in the MALT). And there have been no reports of adverse events from receiving a third shot of mRNA vaccine or a second shot of Janssen vaccine. So what's the delay and why are so many experts still not recommending booster shots across the board? Three reasons have been given:
The focus of most public health and infectious disease experts has been on the acute viral period of C19. That's largely because, while some other infections can cause long-term health consequences, most do not, and most doctors by training are concerned about preventing severe illness and death. But C19 has shown itself to be different from other common RTIs in so many ways (it's airborne, it's more contagious, it's more deadly, it shape-shifts more quickly than expected, etc.) and the fact that it causes such a high degree of chronic and potentially chronic illness is just one more distinguishing feature of this novel virus. It is not unreasonable to be concerned that in the end, the second and third phases of C19 will wind up taking a larger toll on society than the (sometimes deadly) first phase. If boosters were available today, I'd take one immediately. 943. Iceland recommends booster shots for all citizens who got Janssen at 8 weeks post-vaccination. https://www.landlaeknir.is/um-embaettid/frettir/frett/item47133/maelt-med-orvunarbolusetningu-fyrir-einstaklinga-sem-fengu-covid-19-boluefni-janssen 944. Moderna seeks authorization of the first variant-specific booster shot; but it's tuned to Beta, not Delta. https://www.healio.com/news/primary-care/20210225/moderna-sends-variantspecific-vaccine-to-nih-for-clinical-study 945. Pfizer submits data from Phase I clinical trials on booster doses which they now recommend for the general population. Boosters triggered the production of significantly higher levels of circulating neutralizing antibodies against Delta. https://www.cnbc.com/2021/08/16/covid-vaccine-booster-shot-pfizer-submits-data-to-fda-for-approval.html 946. Dr. Fauci: "Everyone will need a booster shot." https://www.cnbc.com/2021/08/12/covid-booster-shot-fauci-says-it-is-likely-everybody-will-eventually-need-a-third-vaccine.html 947. Israel is now doing booster shots for all persons 50 and over and for all healthcare workers. https://www.voanews.com/middle-east/israel-rolls-out-covid-booster-shots-anyone-over-50 948. Biden Administration to approve booster shots for most Americans at 8 months post-vax, beginning with healthcare workers. https://www.nytimes.com/2021/08/16/us/politics/booster-shots.html August 16, 2021 Weekly C19 Briefing summary: Cloth and surgical masks are minimally helpful; FDA approves mAb therapy for prophylaxis and approves boosters for immunocompromised (and the booster shots are working); Moderna offers better protection than Pfizer against Delta; new quarantine periods for Delta depend on whether or not the patient has been vaccinated; more data show the vaccines do not impact fertility; if Florida were its own country, it would have the 5th highest rate of C19 in the world; HHS workers must get vaccinated or lose their jobs; higher circulating antibody levels are what prevents infections while durable B and T cells prevent severe disease during the viral phase.
927. The quality of the mask is important. 20% protection with cloth masks, 40% with surgical masks, 95% with the masks we are wearing. Vaccinated people are having a shorter disease period and spreading the disease less than unvaccinated people; they tend not to be superspreaders but confine their spread to household members. https://www.cnbc.com/2021/08/09/dr-scott-gottlieb-says-the-covid-delta-surge-may-be-the-final-wave-in-us.html 928. The FDA authorizes use of mAbs for prophylaxis in people with known exposure. https://www.empr.com/home/news/fda-authorizes-use-of-covid-19-antibody-therapy-for-postexposure-prophylaxis/ 929. In a study of more than 50,000 patients in the Mayo Clinic Health System, Moderna's effectiveness dropped from 86% effectiveness against infection against Alpha to 76% against Delta (Jan/Feb vs. July). Over the same time period, the effectiveness of Pfizer dropped from 76% to 42%. https://www.medrxiv.org/content/10.1101/2021.08.06.21261707v1.full.pdf 930. Among 198 residents in a long term care home, stronger immune responses were mounted following Moderna than Pfizer, with higher levels of total and neutralizing antibodies after Moderna. https://www.medrxiv.org/content/10.1101/2021.08.06.21261721v1 931. More great epidemiological work from the UK: the REACT study evaluates population-level info to reveal where, how, and which variant of Scov2 is spreading. We have no similar effort here. The CDC’s cohort studies are small, narrow, and occasional. We are still not investigating breakthrough cases unless they result in severe disease or death. This website is worth perusing–it's a treasure trove of real time data. One new data point: Delta infections cause longer viral shedding than prior variants. https://www.imperial.ac.uk/medicine/research-and-impact/groups/react-study/real-time-assessment-of-community-transmission-findings/ 932. Viral loads decline more rapidly in vaccinated (mRNA) vs. unvaccinated people infected with Delta. Vaccinated reached a Ct value of 30 on day 9 post-diagnosis vs. day 15 for unvaccinated. If we use Ct as a surrogate for infectiousness with the assumption that a Ct value of 30 or more means viral titers have dropped low enough to make the disease no longer transmissible, we should consider amending our current quarantine instructions as follows: 10 days for vaccinated; 16 days for unvaccinated (from on set of illness covid-19-science-news-and-research-weekly-briefings-august-16-2021.html or date of positive test). https://www.medrxiv.org/content/10.1101/2021.07.28.21261295v1 933. Neither infection nor mRNA vaccination causes any harm to eggs or ovarian follicles. https://academic.oup.com/humrep/advancearticle/doi/10.1093/humrep/deab182/6345462?searchresult=1 934. As Delta rips through Florida (one in every five cases in the country is currently taking place in Florida), the Governor of that state has issued an executive order banning mask mandates for kids in schools and threatening to withhold teacher salaries if schools require masking. The CDC, the American Academy of Pediatrics, and other major health organizations and leading experts are all in agreement that masking is critical for safety as the case rates among kids rises exponentially due to Delta. Now, >800 doctors sign a letter criticizing what is clearly a political–not rational, science-based–anti-masking position. https://www.independent.co.uk/news/world/americas/us-politics/ron-desantis-florida-doctor-petition-b1901724.html 935. The WHO is conducting a clinical trial in 52 countries to study 3 anti-inflammatory drugs as potential treatments for hospitalized C19 patients: artesunate, imatinib and infliximab. The primary endpoint will be death. This will be part of the Solidarity PLUS trial. Artesunate is already used for malaria, imatinib for certain cancers, and infliximab for autoimmune diseases such as Crohn's Disease and RA. The original Solidarity trial last year found that all 4 treatments evaluated - remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon - had little or no effectiveness against C19. Unfortunately, they did not include colchicine which has shown a strong signal from the data that it could prevent hospitalizations.... https://www.who.int/news/item/11-08-2021-who-s-solidarity-clinical-trial-enters-a-new-phase-with-three-new-candidate-drugs 936. HHS Secretary Xavier Becerra announced today that vaccinations will be mandated for its workforce. This will include employees of NIH and will affect > 25,000 employees, contractors, trainees, and volunteers whose duties put them in contact or potential contact with patients at an HHS medical or clinical research facility. This comes on the heels of the Pentagon announcement earlier this week that by mid-September all 1.3 million military members would have to get vaccinated. The U.S. Department of Veterans Affairs also announced a similar move last month and various airlines are moving in the same direction. https://www.politico.com/news/2021/08/12/hhs-mandates-covid-19-vaccinations-for-health-care-workforce-504138 937. From NEJM: Confronting the catastrophe of long-covid/PCS. C19 is not the first microorganism to cause long-term clinical sequelae but, perhaps because it is so much more widespread or perhaps because Scov2 enters cells through ACE2 and ACE2 is so ubiquitous, it is doing so at a much higher prevalence rate. How will we deal with what looks very much like ME/CFS on a widespread scale? Will we continue to marginalize these patients or treat their debilities as purely psychogenic? My take: We will need more longitudinal studies like the one from the UK biobank showing a consistent pattern of gray matter destruction among C19 infected patients to help validate the suffering of long-haulers if they are going to be taken seriously by many healthcare providers. If we do not do this, their care and management will be overseen by allied providers and fringe providers who are less well trained and less well equipped to take care of them. file:///Users/gregoryberkoff/Downloads/Long%20code.pdf 939. According to Shane Crotty at La Jolla Institute for Allergy and Immunology, after each exposure to a pathogen, the immune system conducts a kind of cost/benefit analysis on how robust and how durable post-infection immunity should be. [My thought: The two-shot regimen is superior to the single dose regimen in part because the second exposure informs the immune system that the pathogen (or spike protein antigen) in question is highly prevalent. We now know that the ideal spacing between doses for Pfizer is 8 weeks (see #901 from a previous briefing) and this could be one reason why Moderna, whose second shot is given at 4 weeks, is holding up better than Pfizer, whose second shot is at three weeks.] Shane Crotty: A third exposure some months later via a booster is likely to make the immune response not only bigger (about twice the level of neutralizing antibodies is seen following the booster compared to that following the second dose of a two shot regimen) but also more durable as it informs the immune system that the pathogen (the spike protein) is prevalent and durable in the environment. What's the best way to understand the relative roles of circulating antibody levels, memory B cells, and T cells? Circulating neutralizing antibody levels are the line of defense that protects against infection. With sufficient exposure, the virus will colonize in the mucous membranes of the nose, throat, mouth, and nasopharynx. High levels of circulating neutralizing antibodies can quickly attack those (technically external) cells and stop the colonization from penetrating into the interior to cause an infection. This, in my opinion, is the chief argument in favor of booster shots. Memory B and T cells, on the other hand, form the primary arsenal of defenses once infection has occurred. When the virus breaks through the epithelial level to enter the body's interior, helper T cells alert memory B cells and plasma cells to produce antibodies while killer T cells destroy infected cells and viruses contained therein. This cell-mediated response takes a few days to mount, however, and with Delta replicating more quickly with a shorter incubation time, many breakthrough infections are symptomatic. So far, we have seen that antibodies wane some months after infection or vaccination but T and B cells persist. The durability of immune cells is what ensures that most vaccinated people will not progress to severe illness if they get infected; the waning of antibody titers over time means that months after primary vaccination or primary infection, the risk of breakthrough infections and reinfections increases. If our focus is exclusively on the viral phase of C19, we do not need boosters yet. If, however, we are also focused on the post-viral phase, then we need boosters to increase circulating antibody levels to help prevent infections. Notice how Carlos Del Rio has to evade direct questions from Bob Wachter about what is clearly a need for boosters among those of us who got vaccinated half a year ago. The focus is exclusively on the viral phase, as though the very subject of long-covid/PCS or the growing impressive data showing brain injury among those with even mild or asymptomatic infection, are taboo. https://www.youtube.com/watch?v=-sQsIETW47Q&ab_channel=UCSFSchoolofMedicine 940. After a third shot (using Moderna) patients with organ transplants had a 71% neutralizing antibody protection against Scov2 compared with 13% among those who received the standard two dose regimen followed by placebo. https://www.nejm.org/doi/full/10.1056/NEJMc2111462?query=featured_home941. Elderly patients who waited 11-12 weeks for their second shot developed triple the antibody response compared to those who took the second shot at three weeks (Pfizer). https://www.medrxiv.org/content/10.1101/2021.05.15.21257017v1 942. FDA approves boosters for limited group of immunocompromized patients under EUA, ahead of the CDC. It looks like it will be a standard dose of either mRNA vaccine. They are expected to give full certification of the vaccines (at least Pfizer and Janssen) in the next two weeks. This would allow physicians to make their own decisions about when, which, how much, and to whom to give booster shots. As yet, there is not guidance on timing in relation to other vaccines but I anticipate the recommendation will be to give at least a 30 days window. https://www.nytimes.com/2021/08/12/us/covid-vaccine-booster-pfizer-moderna.html August 9, 2021 Weekly C19 Briefing summary:
Local and national case rates continue to climb with 2,750 cases in one day (yesterday); vaccination protects against getting infected, lowering risk of catching C19 by 3-10x depending on the source; the FDA is expected to approve booster shots and certify Pfizer and Janssen very soon; herd immunity now estimated to be 90% of population immunized; the case rate among children is going up very fast; review of what we know about children and C19 and what we should be recommending; review of the new VOCs coming after Delta; the concept of 'leaky vaccines' is validated through a very well done new study. 906. There were 2,754 new cases yesterday in San Diego with a weekly average of more than 1,400/day. This is almost certainly a significant undercount since Delta can cause a clinical picture that looks just like allergies or a cold with runny nose, sneezing, sore throat, and many people assume they have something that they "get all the time" or their doctors assume they have a cold. https://www.nytimes.com/interactive/2021/us/san-diego-california-covid-cases.html 907. Although the MA team has doing PCR testing for some time, with new team members, I thought it would be good to review the technique for performing the swab which can make the difference between a positive test and a false negative test. The key is to advance the swab along the floor of the nose toward the throat, not upward toward the brain. Joyce, please make sure the entire team knows how to do this properly. https://www.youtube.com/watch?v=J7lLZEZ6u_w&ab_channel=NebraskaMedicineNebraskaMedicalCenter 908. Vaccinated are 3x less likely to get infected than unvaccinated by the most current estimate from the REACT1 Study, in this paper from Imperial College London: https://spiral.imperial.ac.uk/bitstream/10044/1/90800/2/react1_r13_final_preprint_final.pdf 909. But 8x less likely to get infected according to Covid Tracker (Johns Hopkins University). https://www.covidtracker.com/ 910. And about 10x less likely to get infected according to the SDCDPH COVID-19 Watch. https://www.sandiegocounty.gov/content/dam/sdc/hhsa/programs/phs/Epidemiology/COVID-19%20Watch.pdf 911. Two-thirds of people with mild or moderate viral periods (non-hospitalized) are still symptomatic 30-60 days after OOS: fatigue, SOB, and brain fog were the most common symptoms. Yet another name for the syndrome is introduced in this paper as well: post-acute sequelae of SARS-CoV-2 or PASC. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254347 912. The latest update on booster shots is that the FDA will likely approve them for immunocompromised under EUA in the next couple of weeks. The FDA is also expected to approve Pfizer certification by the beginning of September. If that happens, providers will be able to prescribe extra shots to whomever they think needs them. https://www.nytimes.com/2021/08/06/health/covid-booster-shot-immunocompromised.html?searchResultPosition=2 913. What is the number to reach herd immunity? Because Delta is twice as transmissible as the D614G ancestral strain, the estimated threshold for herd immunity has been increased from 67% to 90%, according to the Infectious Diseases Society of America. https://www.idsociety.org/multimedia/videos/idsa-media-briefing-vaccines-the-delta-variant-and-chasing-herd-immunity/ 914. A booster dose of Novavax provided 4x the overall antibody levels and 6x greater functional ACE-2 binding inhibition antibodies against Delta than that observed shortly after the primary 2-dose vaccination series. https://ir.novavax.com/2021-08-05-Novavax-Announces-COVID-19-Vaccine-Booster-Data-Demonstrating-Four-Fold-Increase-in-Neutralizing-Antibody-Levels-Versus-Peak-Responses-After-Primary-Vaccination 915. In the last week of July, children represented 19% of C19 cases in the US, representing a 25% jump from the prior average. Cases among children doubled in the last week of July compared to the previous week. This is likely due to Delta which is more transmissible, according to the American Academy of Pediatrics who recommends two things: children should return to school and they should be required to wear masks. https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/covid-19-planning-considerations-return-to-in-person-education-in-schools/ Moderate Dive: Kids and C19 (Summary of the CDC data and guidance) I. Kids 5 and older can catch it and spread it, just like adults: In the US through March 2021, the estimated cumulative rates of infections and symptomatic illness in children ages 5-17 years were comparable to infection and symptomatic illness rates in adults ages 18-49 and higher than rates in adults ages 50 and older. Rates of infection and symptomatic illness in 0-4YOs are roughly half of those in 5-17YOs, but comparable to those in adults 65 and older. Children and adolescents can spread Scov2 when they are asymptomatic, presymptomatic, mildly symptomatic, moderately symptomatic, or very sick, just like adults. II. In-person learning is a good idea. But it's less of a good idea when community transmission is very high and not a good idea without layered risk mitigation measures: A study comparing C19 hospitalizations between counties with in-person learning and those without in-person learning found no effect of in-person school on hospitalization rates when baseline county hospitalization rates were low or moderate. However, this changes when the community transmission rate goes up and significant secondary transmission has occurred in school settings when prevention strategies are not implemented or are not followed. In Israel, a school was closed less than two weeks after reopening when two students initiated an outbreak of 153 infections among students and 25 among staff members, from among 1,161 students and 151 staff members that were tested. Importantly, prevention strategies were not adhered to–specifically, they lifted the masking mandate. The majority of cases that are acquired in the community and are brought into a school setting result in limited spread inside schools when multiple layered prevention strategies are in place and most studies have shown success in limiting transmission in schools have required that staff and students wear masks. Inconsistent mask use likely contributed to school-based outbreaks. III. What about distancing and hand-washing? Distancing is less important with data showing that 1M separation between kids in school was not a higher risk than 6 feet. The recommendation to distance 6 feet was based on a (now understood to be false) assumption that Scov2, like colds and flu, spreads by direct and fomite transmission vectors. Where did the CDC get such an idea? It wasn't from the C19 data but from data on prior common respiratory infections which commonly are spread through touch and droplets from sneezing and coughing up phlegm. Because C19 is a dry respiratory disease (that for a year and a half did not manifest with productive cough or runny stuffy nose), transmission has been primarily through virus-containing aerosols (airborne transmission). My addition: Now, however, with Delta, we are starting to see a new presentation in which C19 in many people looks very much like seasonal allergy or a cold. This could finally make all of that hand washing and surface sanitizing something more than 'hygiene theater.' Let's do it all and add every reasonable layer of protection at our disposal. 916.https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/transmission_k_12_schools.html IV. If kids are highly unlikely to wind up with severe illness from C19, why vaccinate them or make them wear masks? 917. One reason is that they, like adults, seem to be getting PCS/long-covid at a fairly high rate. Difficulty concentrating, problems with memory, and fatigue are among the most common problems and these things have profound consequences for academics and athletics in the near term. There is as yet no way to know what contracting C19 will mean down the road for children and one could make the case, based on the data so far, that they have the most to lose if the damage (to brain tissue, for example) caused by infections turns out to be permanent. https://www.nytimes.com/2021/08/08/health/long-covid-kids.html 918 - 925. Delta Plus, Lambda (the VOI formerly known as C.37), and B.1.621 As noted in previous briefings, Delta has shown a pattern of spreading very fast, peaking, and then declining sharply irrespective of vaccination rates. Time to the peak seems to be about 2 months. That puts us just about a month away from the peak here in the US. What comes next? Likely another brief lull. And then? Infections due to Delta dropped suddenly after the peak in India and the UK but never went away. Now we are seeing Delta rising again in the UK, where they have stopped masking and staying flat at a fairly high rate in India. My crystal ball says we should probably expect the peak in September, followed by a drop in cases but not to pre-Delta levels, followed by a resurgence if we do not reinstitute universal masking and get significantly more people vaccinated (including boosters for those of us who were vaccinated early). Another possibility is that we could see Delta quickly replaced by another new VOC. Delta Plus is a contender, as it is genotypically the same virus as Delta with one additional mutation in the RBD that is thought to enhance its ability to bind even more tightly to ACE2. India has declared Delta Plus as its own VOC but the WHO and CDC have not yet done so. It is not know how prevalent Delta Plus is in the US but it has been estimated to be higher here than anywhere else. However, such estimates are specious since neither the US nor India are doing widespread genomic sequencing. Another candidate is Lambda. A new study from Japan indicates that a unique 7-amino-acid deletion mutation in the N-terminal domain of Lambda's spike is responsible for evasion from neutralizing antibodies and may make this VOI significantly more resistant to vaccine-induced immunity and natural immunity from prior infections. These findings mirror those of a study released a few weeks ago from Chile. According to the GISAID Initiative, there have been 1037 documented cases of Lambda so far in the US. According to the WHO, Lambda (formerly designated as C.37) has been identified in over 80% of infections in Peru since April. The variant was first identified in Peru in August 2020. The WHO declared the Lambda a VOI (not a VOC) on June 14 because it became a dominant variant in large areas of South America but it has not been established yet whether or not it spread more quickly than the D614G 'wild type' strain, is more virulent, or has significantly better immune evasion. In January, it made up 1% of the genomically sequenced cases in Lima; by March, it was 50%, and by April, it was 80%. But its numbers appear to be waning now. Higher viral titers and better ACE-2 binding capacity are likely factors driving increased transmissibility and this is one way a VOC can outcompete other strains. But as we move closer to herd immunity, competition might shift toward selecting variants that have more immune escape. This, of course, is the dreaded outcome. If Lambda's immune evasion ability is significantly better than that of Delta, we could need an entirely new vaccine and have to start the herculean task of worldwide vaccination all over again. A third candidate for the next wave is B.1.621 –a variant first identified in Colombia early this year that has become dominant there but has not yet earned its own Greek letter designation. The European CDC has listed it as a VOI. It carries several key mutations, including E484K, N501Y and D614G, that have been linked with increased transmissibility and immune evasion. Early reports have shown B.1.621 to have seeded in Florida. Again, because of low levels of genomic sequencing, it is hard to know how prevalent it is there (or elsewhere in the US). Leaky vaccines 926. The concept of leaky vaccines has been around for a while. Essentially, the idea is that if a vaccine helps the host to not get very sick but does not prevent the host from passing the virus to others, intelligent mutation can occur as a result of the virus being exposed to immune cells and antibodies. The term 'leaky vaccine' can also be replaced with 'imperfect vaccine' as it is meant to distinguish it from a 'perfect vaccine.' Perfect vaccines are so-named because they mimic the perfect immunity that humans naturally develop after having certain childhood disease. When a vaccine works perfectly, as do the childhood vaccines for smallpox, polio, mumps, rubella and measles, it prevents vaccinated individuals from not just from getting sick but also from transmitting the virus to others. Delta, which emerged because of too low vaccination rates, can now bypass imperfect vaccine-induced immunity at a fairly high rate and vaccinated people (and those with prior infections) can now catch C19, get sick, and pass it on, improving the virus' ability to mutate intelligently to become (evolutionarily) fitter. This is the first controlled study to validate the leaky vaccine theory, demonstrating how the virus can become more virulent through this process. But it would probably be more advantageous to Scov2 to improve its fitness by mutating toward better immune evasion and/or transmission. That's exactly what we're seeing. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002198 |
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