Covid 19 Articles

To be determinded

Novavax’s Covid vaccine has the highest efficacy of all Covid vaccines against comparable strains

In the US trial, Novavax had 100% efficacy against the original virus and 93.2% efficacy against variants of interest and variants of concern (including against the Beta variant that was predominant in the UK trial). So in the US trial, Novavax’s numbers against the original virus and against the variants of interest and concern improved 4% and 6.7% respectively. 

The Novavax vaccine had 100% efficacy against the original Covid strain in its US phase 3 trial (the one that originated in China), and it had 96.4% efficacy against the original strain in its UK phase trial. By comparison, Moderna had 94.1% efficacy against the original strain and Pfizer had 95% efficacy. So Novavax beat both Moderna and Pfizer against the original strain by between 1.4% and 5.9%.

At the time that the Moderna and Pfizer trials were completed, there were no variants – only the original strain. In both Novavax trials, a sizable percentage of cases were variants, against which all vaccines are at least somewhat less effective. This is because the vaccines were designed to beat the original virus, and the variants have mutated and evolved to become different from the original virus. So it’s not surprising that all the vaccines are at least somewhat less effective against the variants. 

Therefore, when an article notes that the Novavax vaccine had a combined efficacy of about 90% in the US trial and the UK trial, it doesn’t mean that it was less effective than the Moderna or Pfizer vaccines. It means that at least half of the cases were from variants that are somewhat better at resisting the vaccines. The UK number is a blend of 96.4% efficacy against the original virus, and 86.3% efficacy against the Beta variant.

In the US trial, it had 100% efficacy against the original virus and 93.2% efficacy against variants of interest and variants of concern (including against the Beta variant that was predominant in the UK trial). So in the US trial, Novavax’s numbers against the original virus and against the variants of interest and concern improved 4% and 6.7% respectively. 

The UK results were already the highest efficacy, so it was impressive that the US results were even stronger. In the US trial, there were a small number of cases with unknown mutations that were not the original virus nor variants of interest or concern. These brought the average somewhat lower than the 100% efficacy against the original and 93.2% against known variants. 

Since Moderna and Pfizer fared about 1 1/2% to 6% worse than Novavax against the original virus, they will likely perform similarly worse than Novavax against most variants. A study in Israel found that the Pfizer vaccine had only 64% efficacy against the Delta variant. This means that if half of a population has the original virus and half has the Delta variant, Pfizer’s combined efficacy would be about 79.5%. That is the average of 95% efficacy against the original and 64% against Delta. 

Thus, when comparing results, it’s essential to look at how each vaccine did against a particular strain.


For more information, visit https://covidvaccinesinformation.com/posts. If you want to help fight misinformation related to Covid vaccines, go to: https://covidvaccinesinformation.com/ways-to-help.)

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Novavax’s maximum capacity in 2022 is about 3 billion doses. So to do 2 billion, it only has to achieve 2/3rds utilization.

SUMMARY: If Novavax had only 2 billion units in capacity, they would need to be flawless in every location to achieve their goal of 2 billion doses per year in 2022. If that’s the case, there’d be more of an argument when claiming that they can’t reach 2 billion units in 2022 or that they can’t even reach an adequate number by the end of 2021. But they only need to achieve about 65% utilization of all their locations in order to reach their 2022 target.

FULL INFO: The following is a link to a list of the maximum capacity of all of the Novavax facilities that produce the main component of the vaccine, known as the antigen. Note that Novavax has stated multiple times that by 2022, their capacity will exceed 2 billion doses. While their goal is to produce 2 billion units by 2022, they have stated that they can increase this number even further if they choose to and if the need arises.

Novavx also has facilities that are able to produce enough of its 2nd ingredient (known as an adjuvant) to make 3 billion doses per year. These are the only 2 ingredients. Australia and Lithuania have also expressed interest in making their vaccine.

Here are links that reference the capacities of the facilities:

  1. The Czech Republic factory has a capacity of 1b per year.
  2. The UK factory has an annual capacity of 180m doses. There is a 60m minimum for domestic use. The government has the option to buy more, the rest will be exports.
  3. Novavax capacity in the US will be 50m doses per month, and 600m per year.
  4. The Texas factory has seven 2,000L bioreactors for Novavax doses. Each reactor fabricates 3 batches per month with 2m to 3m doses per batch, which is 6m to 9m doses per reactor. Using the low end, 7 reactors times 6m is 42m doses per month, and 504m per year. Using the mid-point is 45.5m per month and 546m per year. The North Carolina factory has fewer reactors. While we don’t know how many, it would be conservative to estimate that it produces 100m per year (80% less than Texas). The following is a Hyperlink that outlines that Texas has 14 2000L reactors, and half are for Novavax doses and half are for Sanofi.
  5. Texas has been making Novavax doses since January.
  6. In December, North Carolina had already been manufacturing doses for a few months, and the head of research and development at Novavax said the NC factory would be making “many, many millions”.
  7. This Hyperlink describes production plans with the government of Canada.
  8. Serum Institute of India: Claimed it would supply 1.1 billion doses of the vaccine. 
  9. Takeda (Japan): Takeda anticipates the capacity to manufacture over 250 million doses of the Novavax vaccine per year 
  10. BioFabri (Spain): The spanish biopharmaceutical company has a manufacturing capacity of 500m Novavax doses. 
  11. SK Bio (Korea): SK Bioscience have agreed to manufacture 40 million doses of the Novavax vaccine for South Korea. They have recently announced that they are going to expand their annual capacity to about 400m-500m doses per year. Not all of these doses will be allocated to make the Novavax vaccine, but the initial pledge of 40m will grow as a result of this expansion. This expansion is due to funding by CEPI (Coalition for Epidemic Preparedness Innovations) of US$173.4m in May of this year. This comes after an already sizable investment from CEPI of $14.2m in March. Such quick and considerable investments indicate a trust in SK Bio’s advancements that extend to Novavax and its vaccine.

If Novavax had only 2 billion units in capacity, they would need to be flawless in every location to achieve their goal of 2 billion doses per year in 2022. If that’s the case, there’d be more of an argument when claiming that they can’t reach 2 billion units in 2022 or that they can’t even reach an adequate number by the end of 2021. But they only need to achieve about 65% utilization of all their locations in order to reach their 2022 target.

To reach 800m doses in 2021, they only need to attain about 27% utilization of the locations. In May, Novavax was already at about 12% utilization. 

About 2/3rds of the roughly 3 billion capacity is run by top manufacturers with long-standing relationships with suppliers. Common sense would indicate that they have a very good likelihood of reaching 65% utilization. Even if they manage to only do 50% utilization, it’s still 1.5b doses, which is a considerate number of doses.

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For more information, visit https://covidvaccinesinformation.com/posts. If you want to help fight misinformation related to Covid vaccines, go to: https://covidvaccinesinformation.com/ways-to-help.)

Vaccine Hesitancy

Most Republican leaders are pro-vaccination, and this will help to increase vaccination rates

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Most of the leading Republicans think people should get the COVID-19 vaccine now. These include:

OTHER REASONS WHY VACCINATION RATES WILL GO HIGHER

With most leading Republicans in favor of vaccination, more and more Republicans are beginning to get vaccinated. There are many other reasons why vaccination rates will probably rise to 80% nationwide. These include:

  • Other issues will arise that Republicans will be able to channel their political energies into. In the past when a particular issue wasn’t benefitting with their political agenda and was actually hurting them, they usually moved on to other issues with greater traction.
  • Governors of GOP states have big incentives to get people vaccinated. It will help their economies, jobs and businesses. This will incentivize the state’s residents to actively engage with their surroundings economically and culturally since there will be no fear of an outbreak. Citizens missing 1-3 weeks of work has a terrible impact on business owners; plus it equates to lost wages for a lot of people. Also, vaccinations will reduce healthcare costs and deaths. Large mortality rates are a huge political liability, especially if they were preventable.
  • Being anti-vax isn’t a strong fit with their ideological framework. Conservatives generally are in favor of public safety.
  • Some of the Republican anti-vax sentiments are related to RNA. Some of this dislike is because it’s a new technology, and some argue or worry that it hasn’t been tested for numerous years unlike other vaccine platforms. In about 1 1/2 to 3 months when the Novavax vaccine (that uses a tried and true technology) is available, that worry will no longer be valid and those against RNA vaccines will lose their main argument.
  • Over the course of the next 12 months, deaths and hospitalizations are going to gradually result in higher and higher vaccination rates. For example, this Alabama doctor said that after someone dies of Covid, their family members usually get vaccinated soon after. Even if people are hospitalized and survive, most of their family and friends will realize COVID-19 is serious and will get vaccinated. https://news.yahoo.com/johnson-johnson-vaccine-may-less-080034738.html
  • People getting long COVID-19 will also be the catalyst for their friends and family to get vaccinated. When they realize that they could get long-term chronic fatigue and body pain, many will decide to avoid the risk. A study of 2 million patients found that infected people who have COVID-19 symptoms, but are not hospitalized, 27.5% of them develop long COVID. Even people who are infected and have zero symptoms, 19% of them later develop long COVID-19. This means that in the coming months, many will come into contact with friends, family and colleagues who have long COVID-19. Such people will be akin to walking advertisements for vaccination. https://www.self.com/story/post-covid-problems-fair-health-study
  • Even people just being sick in bed for a week will lead to more vaccinations. Some don’t have sick days at work, and not being vaccinated will likely hurt their savings. Other people don’t have enough sick days to be out for 1 to 4 weeks. Most don’t want to get sick with COVID-19 and unexpectedly miss key life events or have to cancel/skip planned events. This includes missing vacations, athletes missing key sporting events or tournaments, performers missing performances. For example, the top league in college football, the SEC, will make teams forfeit games if they can’t field a full squad for a game. In college football, a single extra loss can result in a team not making the playoffs and having no shot at the championship.
    https://www.si.com/college/2021/07/19/sec-will-not-reschedule-games-due-to-covid-19-outbreaks 
  • Peer pressure from friends and family will also increase vaccination rates. In addition to verbal pressure, this will include not allowing unvaccinated people to come to their parties, weddings, funerals and other social events.
  • Influence from athletes, musicians and others who they respect. 
  • Not being able to do things like go on cruises, travel, eat at restaurants, attend concerts and other desirable events and plans. For example, certain bars are already demanding proof of vaccination to enter. Another example is the Pac-12 sports league won’t allow coaches to attend its media day if they’re not vaccinated.
    https://news.yahoo.com/california-bars-start-demanding-proof-of-vaccinations-as-delta-surges-will-vax-requirements-spread-155002636.html
    https://sports.yahoo.com/washington-state-coach-nick-rolovich-wont-travel-to-pac-12-media-days-because-hes-unvaccinated-214148882.html 
  • When people go in for their annual physical or for another doctor’s visit, their doctor will try to persuade them to get vaccinated.
  • The incentives being offered (lotteries, free stuff etc.) by governments and businesses to get vaccinated.
  • Mandates by some states and schools, including universities. Likewise, some businesses are requiring their employees to be vaccinated or get fired, which is exactly what took place with the Minnesota Vikings football team. This news report from late July found that a slew of mandates had been recently implemented. A poll found that 2/3rds of people said their employer was encouraging people to get vaccinated. After the FDA moves from emergency use authorization of COVID vaccines to full approval in the next few months, more employers will move from encouraging to mandating.
    https://www.yahoo.com/news/delta-variant-spreads-vaccine-mandates-215232612.html
    https://sports.yahoo.com/vikings-rick-dennison-reportedly-out-as-assistant-coach-after-refusing-covid-19-vaccine-181439552.html
    https://www.kff.org/coronavirus-covid-19/poll-finding/kff-covid-19-vaccine-monitor-june-2021/ 
  • Also, unvaccinated people will find themselves subject to other impediments and restrictions. E.g. in all NCAA sports, unvaccinated players will be subject to contact tracing, regular testing and quarantine rules. If they’ve been near someone with COVID-19, they will miss practice and games for 10 to 14 days. Even if they haven’t been around a sick person, they must be quarantined before traveling to events. This year, Covid infections caused the NC State baseball team to be ejected from the College World Series when they were just one game away from the championship round. If 85% were vaccinated, they wouldn’t have even been subject to tests, they likely wouldn’t have had an outbreak and even if they had an outbreak, the vaccinated players would have been allowed to play. Less than 50% of the players were vaccinated, so they weren’t even close to the 85% requirement.
    https://www.si.com/college/2021/07/14/covid-19-vaccine-big-12-media-days-football
    https://www.gainesville.com/story/sports/2021/07/03/covid-19-vaccine-right-shot-if-players-care-their-teams/7810627002/
  • With the original virus, experts estimated that between 75% and 80% of people needed immunity in order for a population to reach herd immunity. However, the Delta variant is 100% more contagious than the original virus. As a result, experts think about 85% of people will need immunity for herd immunity to occur. Governments and healthcare systems will do everything they reasonably can to get as close as possible to herd immunity. With a higher threshold needed due to Delta, governments and health systems will be trying to achieve higher vaccination rates than they previously planned to reach.
    https://abc7news.com/delta-variant-california-herd-immunity-coronavirus-covid-19-cases/10902470/
  • Prior to the Delta variant, case counts were declining so rapidly and to such low levels that most unvaccinated Americans probably felt they wouldn’t need to be vaccinated because of the very low level of risk in their region. The Delta variant has more severe impacts on people than the original virus due to having viral loads that are on average 1,000% higher than the original.. It also is causing case counts to skyrocket and is putting unvaccinated people in grave danger. As they become more aware of the likelihood and severity of this danger, some of them will probably shift their opinion.
  • A poll found that 30% of unvaccinated adults would be more likely to get vaccinated if one of the vaccines authorized for emergency use receives full FDA approval. The FDA will probably do this in the next 2 to 4 months, so that alone could increase the vaccination rate by 5% to 8%.
    https://www.kff.org/coronavirus-covid-19/poll-finding/kff-covid-19-vaccine-monitor-june-2021/ 
  • While attacking anti-vaxxers, Geraldo Rivera said, “​​We too have rights: to deny the unvaccinated access to our home, school or business.” Related to his point, this is a situation in which majority rule will probably win out. This becomes increasingly true the higher that vaccination rates rise. When the split is 45% vaccinated to 55% unvaccinated, the vaccinated don’t feel highly confident exercising their right to deny unvaccinated people access to their homes, schools and businesses. But some of them still will in order to protect themselves, their families and their employees. https://www.yahoo.com/news/fox-news-geraldo-rivera-says-212701012.html When the split becomes 55% vaccinated to 45% unvaccinated, the vaccinated feel much more confident exercising their right. In addition, they have majority rule at places where the decision is made by a group. When the split reaches 60% vaccinated to 40% unvaccinated, confidence goes even higher and more people and places implement restrictions on the unvaccinated. If the split reaches 70% to 30%, it will likely be a tipping point where restrictions on the unvaccinated become widespread and constant. That in turn would probably result in a 75% vaccination rate, at which point restrictions would likely become the norm and result in increasingly higher vaccination rates.

CURRENT VACCINATION RATES

As of July 26th, over 57% of the American population has had at least one dose of the vaccine, with over 342 million doses administered. Almost 50% have been fully vaccinated.
https://www.mayoclinic.org/coronavirus-covid-19/vaccine-tracker

Children under 18 represent 24% of the total US population. Only 14.3% of them have received their first dose because people under 12 years old are not approved to be vaccinated yet, and people ages 11 to 17 were only recently approved. https://www.npr.org/sections/health-shots/2021/01/28/960901166/how-is-the-covid-19-vaccination-campaign-going-in-your-state
https://www.mayoclinic.org/coronavirus-covid-19/vaccine-tracker

In late June, 65% of American adults reported they had received at least one dose. Of people who are 18 years or older, 70% have received at least one dose as of July 26th. Of the 30% who are completely unvaccinated, 19% say they will probably or definitely get vaccinated. 19% of 30% translates to roughly 6% of people 18 and older. That alone would bring the total to 76%.
https://www.kff.org/coronavirus-covid-19/poll-finding/kff-covid-19-vaccine-monitor-june-2021/
https://www.webmd.com/vaccines/covid-19-vaccine/news/20210726/most-unvaccinated-americans-want-to-stay-that-way-poll

With the 16 different factors described above that will influence people to be vaccinated, it’s reasonable to think rates among people 18 and older will increase another 4% to 9% for a total of 80% to 85%. As noted earlier, 30% of unvaccinated people said they will be more likely to be vaccinated if the FDA gives full approval to one of the vaccines that now is authorized for emergency use. Since the FDA is going to do this by January, 2022, it will probably add several percent to the total rate.

After vaccines are approved for people under 12, it’s also reasonable to think that child rates will rise to a level that is fairly similar to adult rates. In fact, usually the rates of vaccination for children are much higher than for adults. One of many reasons for this is mandates by most schools that require children to be vaccinated in order to attend school. Another reason is that if adults believe in the vaccine enough to be vaccinated, they will probably have their children do the same.

Another poll found that 77% of Americans believe that vaccinations will have a positive effect on the US economy. American usually want to do what they can to support the economy, so that also indicates a total of 80% to 85% is achievable. https://www.pewresearch.org/science/2021/03/05/growing-share-of-americans-say-they-plan-to-get-a-covid-19-vaccine-or-already-have/

 https://www.bloomberg.com/graphics/covid-vaccine-tracker-global-distribution/#us

Overall, the vaccination rate in the US will probably be very high within the next 10 months. Most of the factors described above that will cause vaccination rates to increase are also present in other countries. Moreover, the majority of other countries don’t have a situation where members of a major political party have shown vaccine hesitancy as a political gesture. So they don’t even need to overcome that hurdle. As a result, many of them may be able to reach levels of 80% to 85% faster than the US. For example, in the UK 90% of adults have received the first dose and 70% have had both doses.
https://www.bbc.com/news/health-55274833

Of course, a portion of countries will have a hurdle to overcome that is different from the US hurdle that’s related to politics. But on the whole, the majority of countries should be able to achieve strong vaccination rates once they have enough supply.

Accurate information about Novavax

Most of Novavax's team has been there for 2 to 11 years and uses very different science than the old company

Short-sellers and anti-vaxxers frequently attack Novavax by saying it hasn’t had an approved vaccine in the 30 years since it was formed. This is misleading because its science and management are now almost totally different than 11 years ago. Also, it takes an average of 12 years to get a vaccine from start to approval and Novavax is close to having two vaccines approved.

Some people have criticized Novavax by claiming the same management team and same science have failed for 30 years to get a vaccine approved. They claim this is a serious risk and reason to not invest. However, almost all of management has been there for only 10 years or less, as you can see here. The CEO and the president of R&D have been there 10 years. Their chief commercial officer, VP of commercial strategy and head of corporate development have been there for 7 years.

The chief medical officer and the heads of manufacturing, sales, operations, compliance, IT, and global program management have been there for under 4 years. The Nanoflu manager, chief legal officer and head of CMC have worked there for 11 years. Only 2 of the 19 members of upper management have been there for longer than 11 years: their head of HR for 13 years and VP of discovery for 17 years.

The science that the new management switched to using is very different than before. Here are 3 major changes:1) Their main platform used to be virus-like particle (VLP) and the new management switched to a subunit protein platform 7 years ago. This article from 2009 shows they were using VLP. When Googling Novavax VLP, nearly all the results are from 2008 to 2014. 2) The Novavax Covid vaccine uses a breakthrough that was only patented in 2017. 3) Seven years ago Novavax acquired the company that created Matrix M.

Half the vaccines it worked on during the last decade were for viruses that looked like they had a solid likelihood of becoming major problems but did not. These included MERS and Zika. They had no market or very little market. So the reason those didn’t get approved was that they weren’t needed, and not because they failed. But they gave the team valuable knowledge that prepared it for Covid.

It takes an average of 12 years for a company to get a vaccine to approval, including giant companies with huge resources. E.g., GSK spent almost 30 years working on one vaccine. SVB Leerink published a report showing that for more than 10 key vaccines now widely used, the time from pathogen discovery to approval was 10 to 100 years.

When the Novavax vaccine is approved in the coming weeks, it will mean the current team got a vaccine over the finish line two years faster than the 12-year average. In addition, they should also beat the 12-year mark with their Nanoflu vaccine. It beat the leading flu vaccine Fluzone in 3 head-to-head trials, including a phase 3. The FDA has given it both: 1) fast track status; and 2) an accelerated approval pathway. It is near certain to be approved.

For a small clinical stage biotech to get 2 blockbusters approved in 12 years of work is a huge accomplishment. Yet some claim the team has failed for 30 years. That’s like blaming the new owner and coach of a sports team for previous owners and coaches not winning a championship. For 50 years, the Patriots were terrible. When a new owner hired a new coach in 2000, some fans glumly and irrationally claimed the failures would continue based on the failures of past people. In the 20 years since, it has 17 division titles, 9 Super Bowl appearances and a record 6 championships.

Also, if you view the biographies of Novavax management, you’ll find it has numerous people very experienced at manufacturing, compliance and other needed areas. It has also attracted high quality talent in the last year to augment their team. E.g., they landed Dr. Henrietta Ukwu, formerly head of Merck’s vaccine regulatory development and affairs. She also had similar roles at PPD and a Pfizer subsidiary.

They also hired Troy Morgan who had senior compliance roles at Sanofi, Merck and Biogen. They also got Dr. Lyn Caltabiano, the former head of global project and alliance management for Merck Research, and head of GSK’s alliance management. It got Dr. Filip Dubovsky as chief medical officer, pulling him from AstraZeneca. He’s also been the head of clinical development at MedImmune.

Bill Gates said: “As we look ahead into the next century, leaders will be those who empower others.” I think Novavax has empowered its staff to develop strong vaccines, successfully move them through trials and ramp up production in what is becoming one of the greatest ramp-ups in pharma history. As Endpoints News editor Jason Mast notes, Novavax is in the process of “one of the most herculean feats in the history of industry.” Mast is saying of all industry, not just the vaccine industry. “Amazingly, it’s largely been a success,” he said. “Factories on three different continents are now churning out or preparing to churn out different components of Novavax’s vaccine.”

Vaccine safety

Preliminary Findings of Covid-19 Vaccine Safety in Pregnant People

Initial findings did not show obvious safety signals among pregnant people, but larger studies are recommended.

Many pregnant persons in the United States are receiving coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy. From December 14, 2020, to February 28, 2021, we used data from the “v-safe after vaccination health checker” surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons.

RESULTS

A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant. Injection-site pain was reported more frequently among pregnant persons than among nonpregnant women, whereas headache, myalgia, chills, and fever were reported less frequently. Among 3958 participants enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy, of which 115 (13.9%) resulted in a pregnancy loss and 712 (86.1%) resulted in a live birth (mostly among participants with vaccination in the third trimester). Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported. Although not directly comparable, calculated proportions of adverse pregnancy and neonatal outcomes in persons vaccinated against Covid-19 who had a completed pregnancy were similar to incidences reported in studies involving pregnant women that were conducted before the Covid-19 pandemic. Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases).

CONCLUSIONS

Preliminary findings did not show obvious safety signals among pregnant persons who received mRNA Covid-19 vaccines. However, more longitudinal follow-up, including follow-up of large numbers of women vaccinated earlier in pregnancy, is necessary to inform maternal, pregnancy, and infant outcomes.

The first coronavirus disease 2019 (Covid-19) vaccines available in the United States were messenger RNA (mRNA) vaccines: BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna). In December 2020, the vaccines were granted Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) as a two-dose series, 3 weeks apart for Pfizer–BioNTech and 1 month apart for Moderna, and were recommended for use by the Advisory Committee on Immunization Practices (ACIP).1-4 Pregnant persons were excluded from preauthorization clinical trials, and only limited human data on safety during pregnancy were available at the time of authorization. However, pregnant persons with Covid-19 are at increased risk for severe illness (e.g., resulting in admission to an intensive care unit, extracorporeal membrane oxygenation, or mechanical ventilation) and death, as compared with nonpregnant persons of reproductive age.5 Furthermore, pregnant persons with Covid-19 might be at increased risk for adverse pregnancy outcomes, such as preterm birth, as compared with pregnant persons without Covid-19.6 The Centers for Disease Control and Prevention (CDC) and ACIP, in collaboration with the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics, have issued guidance indicating that Covid-19 vaccines should not be withheld from pregnant persons.7-9

Postauthorization monitoring in pregnant persons is necessary to characterize the safety of these new Covid-19 vaccines, which use mRNA, lipid nanoparticles, and state-of-the-art manufacturing processes. Furthermore, establishing their safety profiles is critical to inform recommendations on maternal vaccination against Covid-19. We report preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons from three U.S. vaccine safety monitoring systems: the “v-safe after vaccination health checker” surveillance system,10 the v-safe pregnancy registry,11 and the Vaccine Adverse Event Reporting System (VAERS).12

MONITORING SYSTEMS AND COVERED POPULATIONS

V-safe Surveillance System and Pregnancy Registry

V-safe is a new CDC smartphone-based active-surveillance system developed for the Covid-19 vaccination program; enrollment is voluntary. V-safe sends text messages to participants with weblinks to online surveys that assess for adverse reactions and health status during a postvaccination follow-up period. Follow-up continues 12 months after the final dose of a Covid-19 vaccine. During the first week after vaccination with any dose of a Covid-19 vaccine, participants are prompted to report local and systemic signs and symptoms during daily surveys and rank them as mild, moderate, or severe; surveys at all time points assess for events of adverse health effects. If participants indicate that they required medical care at any time point, they are asked to complete a report to the VAERS through active telephone outreach.

To identify persons who received one or both Covid-19 vaccine doses while pregnant or who became pregnant after Covid-19 vaccination, v-safe surveys include pregnancy questions for persons who do not report their sex as male. Persons who identify as pregnant are then contacted by telephone and, if they meet inclusion criteria, are offered enrollment in the v-safe pregnancy registry. Eligible persons are those who received vaccination during pregnancy or in the periconception period (30 days before the last menstrual period through 14 days after) and are 18 years of age or older. For persons who choose to enroll, the pregnancy registry telephone-based survey collects detailed information about the participant, including medical and obstetric history, pregnancy complications, birth outcomes, and contact information for obstetric and pediatric health care providers to obtain medical records; infants are followed through the first 3 months of life. Details about v-safe and v-safe pregnancy registry methods have been published previously.10,11

OUTCOMES

V-safe outcomes included participant-reported local and systemic reactogenicity to the BNT162b2 (Pfizer–BioNTech) vaccine and the mRNA-1273 (Moderna) vaccine on the day after vaccination among all pregnant persons 16 to 54 years of age and among nonpregnant women 16 to 54 years of age as a comparator. For analysis of pregnancy outcomes in the v-safe pregnancy registry, data were restricted to completed pregnancies (i.e., live-born infant, spontaneous abortion, induced abortion, or stillbirth). Participant-reported pregnancy outcomes included pregnancy loss (spontaneous abortion and stillbirth) and neonatal outcomes (preterm birth, congenital anomalies, small size for gestational age, and neonatal death) (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). In the VAERS, outcomes included non–pregnancy-specific adverse events and pregnancy- and neonatal-specific adverse events.

STATISTICAL ANALYSIS

Demographic information and pregnancy characteristics are described for both v-safe and VAERS participants. Descriptive analyses were performed with the use of v-safe survey data for persons who identified as pregnant through February 28, 2021 (35,691 persons); persons enrolled in the v-safe pregnancy registry who were vaccinated through February 28, 2021 (3958 persons); and VAERS reports involving pregnant women received through February 28, 2021 (221 persons). Local and systemic reactogenicity was compared between persons who identified as pregnant and nonpregnant women. Descriptive analyses were conducted with the use of SAS software, version 9.4 (SAS Institute). All activities were reviewed by the CDC and were conducted in accordance with applicable federal law and CDC policy.

V-SAFE SURVEILLANCE: LOCAL AND SYSTEMIC REACTOGENICITY IN PREGNANT PERSONS

From December 14, 2020, to February 28, 2021, a total of 35,691 v-safe participants identified as pregnant. Age distributions were similar among the participants who received the Pfizer–BioNTech vaccine and those who received the Moderna vaccine, with the majority of the participants being 25 to 34 years of age (61.9% and 60.6% for each vaccine, respectively) and non-Hispanic White (76.2% and 75.4%, respectively); most participants (85.8% and 87.4%, respectively) reported being pregnant at the time of vaccination (Table 1). Solicited reports of injection-site pain, fatigue, headache, and myalgia were the most frequent local and systemic reactions after either dose for both vaccines (Table 2) and were reported more frequently after dose 2 for both vaccines. Participant-measured temperature at or above 38°C was reported by less than 1% of the participants on day 1 after dose 1 and by 8.0% after dose 2 for both vaccines.

Most Frequent Local and Systemic Reactions Reported in the V-safe Surveillance System on the Day after mRNA Covid-19 Vaccination.

These patterns of reporting, with respect to both most frequently reported solicited reactions and the higher reporting of reactogenicity after dose 2, were similar to patterns observed among nonpregnant women (Figure 1). Small differences in reporting frequency between pregnant persons and nonpregnant women were observed for specific reactions (injection-site pain was reported more frequently among pregnant persons, and other systemic reactions were reported more frequently among nonpregnant women), but the overall reactogenicity profile was similar. Pregnant persons did not report having severe reactions more frequently than nonpregnant women, except for nausea and vomiting, which were reported slightly more frequently only after dose 2 (Table S3).

The vaccine uses tried and true science with a proven track record of safety

It uses the same technology as the popular Flublok influenza vaccine and the hepatitis B vaccine, which have been used safely by huge numbers of people for numerous years.

Some people have claimed that the Novavax vaccine used a new type of technology that hasn’t been proven safe based on past use. This is false. MedPage Today explains:

Novavax’s COVID-19 vaccine candidate could be the first authorized or approved in the U.S. to rely on a “tried and true” method for immunizing people against coronavirus.

This purified protein, or protein subunit, vaccine strategy is used in many other vaccines on the market today — so does it have a role to play in easing hesitancy to COVID vaccines?

Experts in public health, infectious diseases, and vaccinology interviewed by MedPage Today said that while there are some notable caveats, it’s certainly possible that having the option could help, and that they’d welcome anything that would get more people rolling up their sleeves.

For Novavax’s protein subunit vaccine candidate (known as NVX-CoV2373), spike protein is made by infecting cultures of insect (Spodoptera frugiperda) cells with a baculovirus that’s been altered to contain genes for making the spike. The cells then churn out spike proteins, which are purified and mixed with an adjuvant to make the vaccine.

The Novavax candidate contains the “Matrix-M” adjuvant, which is composed of the plant-derived glycoside saponin, cholesterol, and phospholipids.

Paul Offit, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, said this is the exact same technology used in the Flublok influenza vaccine, and is similar to other purified protein vaccines that have been around for a long time, like the hepatitis B vaccine.

Other COVID-19 vaccines using more traditional technology are in development or in use in other countries, though it’s not clear they’ll become available in the U.S.

William Schaffner, MD, an infectious disease expert at Vanderbilt University Medical Center in Nashville, said there could be an advantage in the emotional appeal of a vaccine strategy with an apparent track record.

“Psychologists tell us that facts are essential, but what changes behavior is how people feel about something,” Schaffner told MedPage Today. “They have to feel comfortable and reassured. … Anything that will persuade some people to make them feel more comfortable in accepting a vaccine is something I endorse.”

 

The spike proteins from Covid vaccines are safe

Spike proteins have been used in many vaccines. They mimic a small part of the virus to train the immune system to recognize and beat the virus.

As reported by First Draft News, here is one falsehood being spread:

Some anti-vaccine conspiracy theorists responded to the Novavax US phase 3 trial data by repeating the false narrativethat spike proteins — the mechanism by which the Novavax and other vaccines produce an immune response — are harmful. “Novavax injection just dumps millions of spike proteins right into your body. Can’t wait to see all the myocarditis from that,” reads a tweet from Dr. Jane Ruby, who describes herself as a medical expert and who recently amplified the false claim that Covid-19 vaccines induce magnetism. 

To see the whole article, click here. Here’s a clip from Politifact that rebuts this falsehood:

There’s no evidence to support the claim that spike protein is dangerous. The spike proteins produced as a result of vaccination help stimulate the body’s defenses against COVID-19. The U.S. Centers for Disease Control and Prevention calls them “harmless.”

Ruby, whose Twitter account identifies her as “Dr. Jane Ruby,” is not a medical doctor. She describes herself as a health economist and “New Right political pundit” with a doctorate in psychology. Her LinkedIn profile shows he has a background in pharmaceutical research and nursing.

We messaged Ruby via Twitter but didn’t get a reply.

We have fact-checked other spike protein claims, finding that there is no evidence they present any serious health risk on their own. 

We rated False a claim by Canadian viral immunologist Byram Bridle that the COVID-19 vaccines’ spike protein means people are being inoculated “with a toxin.” Experts said there is no evidence that the vaccines produce a toxin that could cause heart problems and neurological damage, as Bridle alleged.

We also rated False a claim that COVID-19 vaccines’ “spike protein is very dangerous, it’s cytotoxic,” which means toxic to cells. U.S. public health authorities and vaccine experts said there is no evidence that the vaccines’ spike protein is toxic or “cytotoxic.”

The protein-based Novavax vaccine is similar in its approach to the influenza vaccine Flublok, containing a single viral protein, the SARS-CoV-2 surface protein, said Dr. Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia and a member of the U.S. Food and Drug Administration’s vaccine advisory committee.

“This protein has not been shown to be dangerous,” he said. “It’s just a single viral protein similar to the hepatitis B and human papillomavirus vaccines, and are remarkably safe.” 

“The SARS-CoV-2 virus, on the other hand, reproduces itself thousands of times, and is incredibly dangerous.”

The National Institutes of Health said data from the trial “indicate the investigational vaccine was generally well-tolerated.” The most common side effects were mild to moderate pain at the injection site, fatigue, headache and temporary muscle pain. We rate the post False.

To read the full article, go here.

How long Covid-19 will last in the world

Most health experts say Covid will be endemic, meaning it will be with us forever

There’s no track record of infectious diseases being completely eradicated, and everything about COVID-19 shows that it will be no different. There are numerous reasons for this.

Many health experts say Covid is going to be endemic. www.yahoo.com/…  As CBS News explains: “public health experts say… COVID-19 is never going to end. …researchers say there’s simply no track record of infectious diseases being completely eradicated, and everything about COVID-19 shows that it will be no different… Scientists say all of this makes the virus essentially impossible to control.” www.cbsnews.com/…

The Mayo Clinic’s vaccine chief said: “There is no eradication at this point, it’s off the table. The only thing we can talk about is control. amp.usatoday.com/…

The chief medical officer of BioNTech said Covid booster shots will be “necessary” because “it is the nature of immune responses that … they spike and stay for a time, but with time immune responses wane. We see this in the induced and the natural immune response against [Covid], we see this waning of immune responses.” www.cnbc.com/…

Moderna’s CEO said, “the level of antibodies [is] going to go down, that is normal and natural.” He said boosters “are going to be required” and will “be really important to keep the country safe and open.” www.foxnews.com/…

Novavax’s head of R & D agrees: “Everyone will need to be boosted. This is a viral respiratory disease, and we know from the flu that immunity from an infection is good for maybe 12 months, maybe 18 months, and after that people become susceptible again. After that, we’re going to have to boost.” www.politico.com/…
Another reason boosters are needed is mutations. In a March survey of 77 health experts, two-thirds said within a year Covid will mutate enough to make most vaccines ineffective. 18.2% think it may take longer. Since then, variants have gotten much worse, including many that show serious resistance to vaccines. reliefweb.int/…

Tests by 41 researchers indicate that variants escaping vaccines “will be inevitable.” Many richer countries plan to give variant booster shots in 2022 before half of the world even gets their first dose. www.nature.com/…

As a result, a leading market research firm (IQVIA Institute for Human Data Science) says the Covid vaccine market will total $157B by 2025, an average of $31.4B per year. www.reuters.com/…

Also, I think IQVIA is being conservative and that revenues will be higher than $157B. It reports doses in 2021 cost $22 per dose, but it assumes they will be only $9 per dose in 2023, $7 in 2024 and $5 in 2025. Those would be massive drops of 59%, 68% and 77%. I think prices will be much higher because: a) Most OWS companies have repeatedly said they’re going to raise their prices, not the other way around. b) the adenovirus vaccines aren’t suitable as boosters, which you can see here. That greatly reduces competition. c) The RNA vaccines, which are a major part of the market, can’t be profitably made at $5. d) Lots of flu vaccines exist, yet they are still $27 to $69 per dose.

Also, studies have found that about 20% of people with asymptomatic Covid get Long Covid, and a much higher % of people with mild Covid get Long Covid, which can destroy your quality of life for the rest of their life. Covid gets into nearly all organs of the human body. I don’t think that people are going to just focus on hospitalization at all. The only way to keep it under control is vaccinations.

Preparing for the Future — Nanobodies for Covid-19?

Despite the emergency use authorization issued by the FDA for antibody drugs, only a small proportion of the nation’s supply has been used.

Many had hoped that monoclonal antibody drugs would provide an important stopgap to the coronavirus disease 2019 (Covid-19) pandemic by limiting severe disease and thus the number of hospitalizations until safe and effective vaccines could be approved.1 Despite the emergency use authorization issued by the Food and Drug Administration (FDA) for antibody drugs on the basis of their ability to reduce viremia in mildly and moderately ill patients with Covid-19, only a small proportion of the nation’s supply has been used.

Myriad challenges include the therapeutic window (these drugs are more effective when administered during the first 4 to 7 days in the course of illness), the sheer number of patients during a pandemic surge and the relative paucity of infusion centers and medical staff professionals, and the emergence of mutations that affect the spike protein, which could lead to increased transmissibility and the potential for resistance to neutralization by antibodies.2 Therefore, new therapies that are effective against variants and offer an alternative to intravenously administered antibody drugs are highly desired.

A study by Koenig and colleagues3 on camelid-derived, single-domain antibodies (or nanobodies) is therefore timely. The researchers immunized alpacas and llamas with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and identified nanobodies that specifically bind to the receptor-binding domain of the virus. They characterized four neutralizing nanobodies (labeled E, U, V, and W) structurally and functionally with multiple in vitro assays. Three of the nanobodies (U, V, and W) recognize a common epitope located near the threefold axis of the prefusion trimeric spike, whereas nanobody E recognizes the extended loop (residues R466 through P491) overlapping the receptor-binding domain (Figure 1C).

The nanobodies bound the receptor-binding domain of the virus with an equilibrium dissociation constant of between 2 and 22 nmol and neutralized SARS-CoV-2 infection by 50% in a plaque-reduction assay at concentrations ranging from 48 to 185 nmol, results similar to those achieved with monoclonal antibodies.5 In contrast to the V nanobody, nanobodies E, U, and W have the potential to prevent SARS-CoV-2 from binding angiotensin-converting enzyme 2 (ACE2) on host cells, in agreement with the location of the epitopes to which they bind and their mode of engagement with the receptor-binding domain. The nanobodies neutralize the virus by inducing a premature structural transition from a prefusion conformation to an irreversible postfusion conformation, the latter of which is incapable of binding ACE2 and thus incapable of triggering membrane fusion.

The authors then made biparatopic nanobodies (i.e., nanobodies that have two antigen-binding sites in one molecule) by fusing nanobodies that targeted distinct epitope regions (e.g., E+V, V+E, E+W, and W+E). Using cryoelectron microscopy, they showed that the most potent biparatopic nanobody (V+E) binds to all three spike proteins of the trimer (nanobody-to-trimer, 1:3 stoichiometry) with all the receptor-binding domains in the “up” conformation, indicating that the binding of nanobodies stabilizes the receptor-binding domain and prevents up–down motion, most likely contributing to proteolytic cleavage of the spike and premature transition to an irreversible postfusion conformation. The V+E biparatopic nanobody neutralized SARS-CoV-2 infection at a dilution 62 times greater than that achieved by the individual nanobodies, possibly because of the improved avidity to the spike protein (an affinity that is at least 22 times greater than that of individual nanobodies).4

While passaging a chimeric virus in Vero E6 cells in the presence of nanobodies E, U, V, and W, but not in the presence of the biparatopic (V+E or E+V) nanobodies, the authors found escape variants that had mutations within the epitope regions. This observation highlights the advantage of simultaneously targeting more than one vulnerable epitope. Of note, the footprint of the V nanobody does not include amino acids 417, 484, and 501 of the spike protein (Figure 1C), which are changed in the strains recently identified in Britain, South Africa, and Brazil, suggesting that the biparatope antibody V+E (or E+V) would be effective against these antigenic variants. The epitope recognized by nanobody V is relatively more constrained than the E epitope (which includes residues E484 and N501), meaning it is less likely to tolerate changes caused by mutation. Therefore, mutations that arise in the part of the S gene that encodes this region (i.e., the region of the spike to which the V nanobody binds) are less likely to survive selection. JJJ

Koenig et al. have contributed to the growing number of studies that have isolated nanobodies against SARS-CoV-2. Owing to the relatively small size of nanobodies, they have favorable biophysical properties and are cheaper to produce than standard monoclonal antibodies. Their small size and their long, heavy-chain complementarity-determining regions enable them to target concave epitopes such as the receptor-binding site of the spike protein.

Nanobodies can be made with the use of prokaryotic or eukaryotic expression systems because they lack the glycan-harboring Fc domain, making them easier to manufacture than standard monoclonal antibodies. The absence of an Fc region eliminates the risk of antibody-dependent enhancement of infection, but it also shortens the half-life, which could plausibly be addressed through attachment to or amalgamation with polyethylene glycol or human serum albumin. Moreover, nanobodies can be nebulized and delivered straight to the lungs of a patient with Covid-19 with an inhaler, thus presenting a better logistic alternative to intravenously administered antibodies. Aerosol formulation of nanobodies has shown promising nonclinical results.

Although nanobodies are under clinical investigation for use in a wide range of diseases from cancer to infectious diseases, it was the approval of caplacizumab (an anti–von Willebrand factor bivalent nanobody) by the European Medicines Agency and the FDA for the treatment of thrombotic thrombocytopenic purpura and thrombosis that marked the foray of nanobodies into clinical medicine. The format of the biparatopic nanobody V+E engineered by Koenig et al., although distinct from that of a conventional nanobody, is similar to that of the FDA-approved single-chain, variable fragment–based bispecific antibody blinatumomab (Figure 2).

All things considered, the available structural and clinical data suggest that the biparatopic antibody could potentially offer a better alternative to conventional monoclonal antibodies for the treatment of Covid-19. Recently, experts representing various organizations including regulatory bodies, academia, and pharmaceutical and biotechnology companies have made a call to develop small-molecule drugs that inhibit the machinery that the virus uses to replicate. Such agents are convenient to administer and insensitive to viral mutations. The biparatopic antibody, when formulated for aerosol or subcutaneous administration, will lend those benefits just as effectively.

Medicine and Vaccine Research

Antibody Responses in People with Past Natural Covid-19 Infection:

Neutralizing antibody responses in previously infected participants who received one dose of vaccine was higher than in previously uninfected patients who received two doses.

Whether or not persons who have already been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) should be vaccinated is unclear. Only a few studies have shown that vaccinees who were previously infected with SARS-CoV-2 had a significantly higher antibody response than previously uninfected vaccinees.1-4 In an observational cohort study, we enrolled 100 health care workers, including 38 (9 men and 29 women) with a documented history of SARS-CoV-2 infection (mean duration between infection and vaccination, 111 days).

The mean age of these previously infected participants was 35.1 years (95% confidence interval [CI], 31.7 to 38.6). Our study also included 62 participants (25 men and 37 women) who had not been previously infected. The mean age of those participants was 44.7 years (95% CI, 41.0 to 47.6).

Both groups of participants received the messenger RNA vaccine BNT162b2 (Pfizer–BioNTech). Serum samples were obtained from the previously infected participants 10 days after the administration of the first dose and from the previously uninfected participants 10 days after the administration of the second dose. Thereafter, all the participants were screened for the presence of specific anti–SARS-CoV-2 spike IgG by means of a chemiluminescence microparticle immunoassay.

No significant difference in circulating anti-spike IgG antibody titers was observed between the samples from previously infected participants (mean level, 20,120 arbitrary units per milliliter; 95% CI, 16,400 to 23,800) and those from previously uninfected participants (mean level, 22,639 arbitrary units per milliliter; 95% CI, 19,400 to 25,900) (median levels are shown in Figure 1A). Circulating anti-spike IgG antibodies were not detected in only one previously infected participant; that participant did not have an antibody response to natural infection with SARS-CoV-2.

The same serum samples were also analyzed for the presence of specific anti–SARS-CoV-2 neutralizing antibodies. We observed a difference in levels of neutralizing antibodies between samples from the previously infected participants (geometric mean titer, 569; 95% CI, 467 to 670) and those from the previously uninfected participants (geometric mean titer, 118; 95% CI, 85 to 152) (P<0.001) (median levels are shown in Figure 1B). No substantial differences were noted between the titers from the previously infected and the previously uninfected participants according to age (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) or sex (data not shown).

The previously infected participants were categorized into three groups according to the time that had elapsed from infection to vaccination: 1 to 2 months (8 participants), more than 2 months to 3 months (17 participants), and more than 3 months (12 participants). The previously infected patient in whom circulating anti-spike IgG antibodies were not detected was not included in this categorization. The circulating IgG mean titers differed between the group vaccinated at 1 to 2 months and the group vaccinated at more than 2 months to 3 months after natural infection (mean level, 15,837 arbitrary units per milliliter [95% CI, 11,265 to 20,410] vs. 21,450 arbitrary units per milliliter [95% CI, 15,377 to 27,523]) (median levels are shown in Figure 1C); however, because the number of participants was limited, a real distinction cannot be made. No further significant difference was observed between the group of participants vaccinated at more than 2 months to 3 months and the group of those vaccinated more than 3 months after infection (mean level, 21,090 arbitrary units per milliliter [95% CI, 14,702 to 27,477]).

The differences among the three groups were more evident with respect to levels of neutralizing antibodies, with geometric mean titers ranging from 437 (95% CI, 231 to 643) in participants vaccinated 1 to 2 months after infection to 559 (95% CI, 389 to 730) in those vaccinated more than 2 months to 3 months after infection to 694 (95% CI, 565 to 823) in those vaccinated more than 3 months after infection (median levels are shown in Figure 1D). Although these findings indicate that the booster response was more efficacious when the vaccine was administered more than 3 months after infection, not enough information is available to draw a definitive conclusion.

The most remarkable finding of this study was the significantly lower neutralizing antibody titer after administration of a second dose of vaccine in previously uninfected patients than the titer after only a single dose of vaccine in previously infected participants. It is unclear how the neutralizing antibody titers influence the ability of the host to transmit the virus. These findings provide evidence that after the administration of a single dose of vaccine, the humoral response against SARS-CoV-2 in persons with a history of SARS-CoV-2 infection is greater than the response in previously uninfected participants who have received a second dose.

Length of Time A Person With Covid Symptoms Should Isolate

The CDC recommends isolation precautions for 10 days after symptom onset, with extension to 20 days for immunocompromised patients or those with severe illness.

A 24-year-old woman with no relevant medical history presented to the emergency department with a 1-week history of cough and shortness of breath. She stated that she had not had any contact with people who were sick but had recently attended a small event. She reported no fever, diarrhea, or loss of taste or smell. On physical examination, she was found to have hypoxemia, with an oxygen saturation of 88%, and crackles were heard on lung auscultation. A chest radiograph showed bilateral interstitial opacities, and a polymerase-chain-reaction (PCR) assay was positive for SARS-CoV-2. She was given supplemental oxygen, delivered by nasal cannula at 2 liters per minute, and was placed in an isolation observation unit overnight for monitoring.

The next day, she continued to require oxygen and was admitted to a ward bed. Her oxygen requirements increased, and she was given supplemental oxygen at a rate of 15 liters per minute through a nonrebreather mask and was admitted to the intensive care unit (ICU). Her condition improved over the course of the week, and her need for supplemental oxygen decreased. The remainder of her course was uneventful, and she was transferred back to a ward bed.

It has now been 1 week since her admission to the hospital, and discharge planning has started. The patient plans to go home to stay with her parents, both of whom are over the age of 65 years, while she recuperates. She is concerned about the risk of transmission of SARS-CoV-2 to her parents. Her father is taking immunosuppressive medication after recent kidney transplantation. She has requested that PCR testing be performed again on a repeat nasopharyngeal swab. The PCR test is performed, and the result is positive.

You must advise the patient about the risk of transmitting the virus to her parents, given the time since the onset of Covid-19 symptoms and the positive repeat PCR test.

Treatment Options

Which one of the following approaches would you take? Base your choice on the literature, your own experience, published guidelines, and other information sources.

  1. Recommend continued isolation.

  2. Reassure the patient of the low risk of transmission.

To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the issue and the points made by the experts, which approach would you choose?

  1. Option 1: Recommend Continued Isolation
  2. Option 2: Reassure the Patient of the Low Risk of Transmission

Recommend Continued Isolation

Recommendations on the duration of isolation for patients with Covid-19 continue to evolve with increased understanding of SARS-CoV-2 transmission dynamics. Early in the Covid-19 pandemic, recommendations from the Centers for Disease Control and Prevention (CDC) included discontinuing isolation when there was clinical improvement and a negative molecular SARS-CoV-2 test. This recommendation was replaced by a time-based approach (rather than a test-based one) when it became apparent that shedding of nonviable SARS-CoV-2 RNA in the upper respiratory tract can continue for days to weeks after recovery from illness.1 Early, albeit small studies showed that SARS-CoV-2 detected by PCR in respiratory specimens beyond day 10 after the onset of symptoms did not grow in cell culture and was probably not transmissible.2,3 Large population-based studies conducted by CDC South Korea indicate that the infectious potential of SARS-CoV-2 declines after the first week following symptom onset, irrespective of resolution of symptoms.4

However, a few studies have recently challenged this concept. One study showed viable virus by in vitro growth in cell culture in 14% of patients (4 of 29) with persistent positive SARS-CoV-2 PCR tests from upper respiratory specimens obtained after the first week following the initial positive PCR test; one patient was never hospitalized, and one had been hospitalized with mild symptoms.5 Complete viral genome sequencing indicated that these cases represented the same infection rather than reinfection. Age, immunocompromised status, and severe illness have been associated with prolonged SARS-CoV-2 RNA shedding1; however, data are insufficient regarding factors associated with prolonged shedding of viable SARS-CoV-2. One recent study showed that some patients with immunosuppression after treatment for cancer could shed viable SARS-CoV-2 for at least 2 months.6 A study of 129 severe cases of Covid-19 showed that the probability of detecting viable virus beyond day 15 after symptom onset was 5% or less.7 

The CDC currently recommends isolation precautions for 10 days after symptom onset (with fever resolution lasting at least 24 hours without the use of fever-reducing medications), with extension to 20 days for immunocompromised patients or those with severe illness. The patient described in the clinical vignette had severe infection according to the World Health Organization severity scale and CDC criteria; thus, continuing isolation for a total of 20 days seems reasonable and in accordance with current evidence. No studies to date have reported person-to-person transmission occurring from the observed late shedding of viable SAR-CoV-2; thus, it may be reasonable to customize decisions regarding duration of isolation on the basis of individual circumstances. In the current case, a household member is a kidney transplant recipient, a condition in which Covid-19 infection is associated with high morbidity and mortality, which further justifies a 20-day isolation period.

Repeat SARS-CoV-2 PCR testing to determine the duration of isolation should not be recommended for this patient because, as noted, a positive PCR test does not mean that she is infectious, and viral tissue culture is not available to assess for viable virus in clinical laboratories. Repeat PCR testing can result in unnecessarily prolonged isolation and anxiety for patients and medical teams. Public awareness of the shortcomings of Covid-19 diagnostic tests and the distinction between shedding of viral RNA and viable virus is essential to ensure that patients and health care workers are comfortable with our current approach to isolation precautions for patients with Covid-19.

 

Clinical Implications of Basic Research

Infection Rates Among Vaccinated Nursing Home Residents Are Better Than Unvaccinated

Since the deployment of vaccines against Covid-19 in nursing homes nationwide, aggregate public data have shown decreases in the incidence of cases of SARS-CoV-2 infection and related deaths.

Since the deployment of the messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2 in nursing homes nationwide starting in mid-December 2020, aggregate public data have shown decreases in the incidence of cases of SARS-CoV-2 infection and related deaths.3 However, there have been minimal individual-level data available for understanding vaccine effectiveness in nursing home residents, who were absent from the clinical trials and who often have reduced immune responses.4 Using electronic health record data from Genesis HealthCare, a large long-term care provider in the United States, we report the incidence of SARS-CoV-2 infection among vaccinated residents and unvaccinated residents of 280 nursing homes across 21 states.

From immunization records, we identified residents who had received at least one dose of mRNA vaccine as of February 15, 2021; those who had received both doses by February 15, 2021; and those who were present at their facility on the day of the first vaccination clinic but who were not vaccinated as of March 31, 2021. We identified incident SARS-CoV-2 infections through March 31, 2021, on the basis of polymerase-chain-reaction assay and antigen-test records.

Residents were tested every 3 to 7 days when there were confirmed cases in their facility and were tested if they had any new symptoms or potential exposure. Residents who had been infected in the 90 days before the study window were excluded. We counted incident infections after receipt of each dose among vaccinated residents and after the date of the first vaccination clinic among unvaccinated residents.

Nurses assessed residents daily and documented new symptoms in structured change-in-condition notes. From these notes, we deemed residents to be symptomatic if SARS-CoV-2–related symptoms developed during the period from 5 days before to 14 days after a positive test. Detailed methods are described in the Supplementary Appendix, available with the full text of this letter at NEJM.org.

The sample included 18,242 residents who received at least one dose of mRNA vaccine; 14,669 residents (80.4%) received the Pfizer–BioNTech vaccine, and 3573 (19.6%) received the Moderna vaccine. Of these 18,242 residents, 13,048 also received the second dose of vaccine. A total of 3990 residents were unvaccinated. Table S1 in the Supplementary Appendix summarizes the characteristics of the residents.

The incidence of infection decreased over time among both vaccinated residents and unvaccinated residents (Table 1). After receipt of the first vaccine dose, there were 822 incident cases (4.5% of vaccinated residents) within 0 to 14 days and 250 cases (1.4%) at 15 to 28 days. Among the 13,048 residents who received both doses of vaccine, there were 130 incident cases (1.0% of vaccinated residents) within 0 to 14 days after receipt of the second dose and 38 cases (0.3%) after 14 days (which included 19 cases occurring 15 to 21 days after receipt of the second dose) (Fig. S1). Among unvaccinated residents, incident cases decreased from 173 cases (4.3% of unvaccinated residents) within 0 to 14 days after the first vaccination clinic to 12 cases (0.3%) at more than 42 days after the clinic.

Across all the study groups, most infections were asymptomatic, and the incidence of both asymptomatic and symptomatic infections decreased. Nursing homes that were located in counties with the highest incidence of SARS-CoV-2 infection had the most incident cases but still had large decreases (Table S2). We observed inconsistent patterns in the incidence of infection among residents relative to rates of vaccination among staff members (Table S3).

These findings show the real-world effectiveness of the mRNA vaccines in reducing the incidence of asymptomatic and symptomatic SARS-CoV-2 infections in a vulnerable nursing home population. Our observation of a reduced incidence of infection among unvaccinated residents suggests that robust vaccine coverage among residents and staff, together with the continued use of face masks and other infection-control measures, is likely to afford protection for small numbers of unvaccinated residents in congregate settings. Still, the continued observation of incident cases after vaccination highlights the critical need for ongoing vaccination programs and surveillance testing in nursing homes to mitigate future outbreaks.

Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1–2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission.

BACKGROUND

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1–2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission.

METHODS

In this phase 2a–b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)–negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection.

RESULTS

Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, −0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups.

CONCLUSIONS

The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399. opens in new tab.)

 

The coronavirus disease 2019 (Covid-19) pandemic, caused by the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had resulted in more than 144 million documented cases and 3 million deaths worldwide as of April 23, 2021.1,2 Vaccination remains a cornerstone of control strategies. Current vaccines primarily target the SARS-CoV-2 spike protein on the basis of the prototype Wuhan strain.3 The messenger RNA (mRNA) vaccines (BNT162b2 and mRNA-1273) have shown vaccine efficacy of 94 to 95%4,5 against Covid-19 of any severity, and corresponding vaccine efficacy for vector-based vaccines has been reported to be 70% for ChAdOx1 nCoV-19, 92% for Gam-COVID-Vac, and 67% for Ad26.COV2.S, with the Ad26.COV2.S vaccine measured against moderate-to-severe Covid-19.6-8

Among the Covid-19 vaccines under development is a recombinant SARS-CoV-2 nanoparticle vaccine (NVX-CoV2373, Novavax). The vaccine is produced by engineering a baculovirus that contains a gene encoding full-length SARS-CoV-2 spike glycoprotein (prototype Wuhan-Hu-1 sequence) stabilized in the prefusion conformation. Cultures of cells obtained from the Spodoptera frugiperda moth are infected with recombinant baculovirus to express SARS-CoV-2 spike protein trimers, which are then extracted and chromatographically purified. When formulated with polysorbate 80 (PS 80), the purified trimers assemble into protein nanoparticles consisting of rosettes of spike trimers held together by hydrophobic interactions with a PS 80 micellar core. The nanoparticles are then further coformulated with the saponin-based adjuvant Matrix-M1.9,10 In an ongoing randomized, placebo-controlled, phase 1–2 trial involving healthy adults, the NVX-CoV2373 vaccine, administered in a two-dose regimen 21 days apart, had an acceptable safety profile and was associated with a strong antigen-specific polyfunctional CD4+ T-cell response and induced a neutralizing-antibody level that was four times the level in convalescent serum obtained from patients with predominantly moderate-to-severe Covid-19.11

Recent reports from the United Kingdom, Brazil, and South Africa on the emergence of the B.1.1.7, P1, and B.1.351 (N501Y.V2) variants, respectively, confirm the acquisition of mutations in key antigenic sites in the receptor-binding domain and N-terminal domain of the spike protein.12-17 These antigenic changes may render naturally acquired or vaccine-derived immunity to prototype-like virus less effective against subsequent infection with variant viruses.13,17-19 Here, we describe early findings on the primary efficacy end point and preliminary safety of a randomized, observer-blinded, placebo-controlled, phase 2a–b trial of NVX-CoV2373 in South Africa during a period of predominant circulation of the B.1.351 variant virus.

Methods

TRIAL DESIGN AND PARTICIPANTS

From August 17, 2020, through November 25, 2020, we enrolled participants at 16 sites in South Africa. The trial was designed to provide a preliminary evaluation of vaccine safety and efficacy during ongoing pandemic transmission of SARS-CoV-2. Participants were healthy adults between the ages of 18 and 84 years without human immunodeficiency virus (HIV) infection or a subgroup of adults between the ages of 18 and 64 years with HIV infection whose condition was medically stable. Baseline IgG antibodies against the spike protein (anti-spike IgG antibodies) were measured at study entry to help determine baseline SARS-CoV-2 serostatus for the analysis of vaccine efficacy. As a safety measure, enrollment was staggered into stage 1 (defined by the first third of targeted enrollment) and stage 2 (the remainder of enrollment) for both HIV-negative and HIV-positive participants. Progression from stage 1 to stage 2 in each group required a favorable review of safety data through day 7 from the previous stage against prespecified rules that would trigger a pause in vaccine administration. (Details regarding the participants in each stage are provided in Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Key exclusion criteria were pregnancy, long-term receipt of immunosuppressive therapy, autoimmune or immunodeficiency disease except for medically stable HIV infection, a history of confirmed or suspected Covid-19, and SARS-CoV-2 infection as confirmed on a nucleic acid amplification test (NAAT) performed as part of screening within 5 days before anticipated initial administration of the vaccine or placebo. All the participants provided written informed consent before enrollment. Additional details regarding the trial design, conduct, oversight, and analyses are provided in the Supplementary Appendix and the protocol (which includes the statistical analysis plan), available at NEJM.org.

OVERSIGHT

The NVX-CoV2373 vaccine was developed by Novavax, which sponsored the trial and was responsible for the overall design (with input from the lead investigator), site selection, monitoring, and analysis. Trial investigators were responsible for data collection. The protocol was approved by the South African Health Products Regulatory Authority and by the institutional review board at each trial center. Oversight of safety, which included monitoring for specific vaccination-pause rules, was performed by an independent safety monitoring committee.

The first author wrote the first draft of the manuscript with assistance from a medical writer who is an author and an employee of Novavax. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

TRIAL PROCEDURES

Participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections, 21 days apart, of either NVX-CoV2373 (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or saline placebo (injection volume, 0.5 ml), administered by staff members who were aware of trial-group assignments but were not otherwise involved with other trial procedures or data collection. All other staff members and trial participants remained unaware of trial-group assignments. Participants were scheduled for in-person follow-up visits on days 7, 21, and 35 and at 3 months and 6 months to collect vital signs, review any adverse events, discuss changes in concomitant medications, and obtain blood samples for immunogenicity analyses. A follow-up telephone visit was scheduled for 12 months after vaccination.

SAFETY ASSESSMENTS

The primary safety end points were the occurrence of all unsolicited adverse events, including those that were medically attended, serious, or of special interest, through day 35 (Tables S2 and S3) and solicited local and systemic adverse events that were evaluated by means of a reactogenicity diary for 7 days after each vaccination (Tables S4 and S5). Safety follow-up was ongoing through month 12.

EFFICACY ASSESSMENTS

The primary efficacy end point was confirmed symptomatic Covid-19 that was categorized as mild, moderate, or severe (hereafter called symptomatic Covid-19) and that occurred within 7 days after receipt of the second injection (i.e., after day 28) (Table S6). Starting on day 8 and continuing through 12 months, we performed active surveillance (telephone calls every 2 weeks from trial sites to participants) and passive surveillance (telephone contact at any time from participants to trial sites) for symptoms of suspected Covid-19 (Table S7 and Fig. S1). A new onset of suspected symptoms of Covid-19 triggered initial in-person and follow-up surveillance visits to perform clinical assessments (vital signs, including pulse oximetry, and a lung examination) and for collection of nasal swabs (Fig. S2). In addition, suspected Covid-19 symptoms were also assessed and nasal swabs collected at all scheduled trial visits. Nasal-swab samples were tested for the presence of SARS-CoV-2 by NAAT with the use of the BD MAX system (Becton Dickinson). We used the InFLUenza Patient-Reported Outcome (FLU-PRO) questionnaire to comprehensively assess symptoms for the first 10 days of a suspected episode of Covid-19.

WHOLE-GENOME SEQUENCING

In a blinded fashion, we performed post hoc whole-genome sequencing of nasal samples obtained from all the participants who had symptomatic Covid-19. Details regarding the whole-genome sequencing methods and phylogenetic analysis are provided in Fig. S3.

STATISTICAL ANALYSIS

The safety analysis population included all the participants who had received at least one injection of NVX-CoV2373 or placebo; regardless of group assignment, participants were evaluated according to the intervention they had actually received. Safety analyses were presented as numbers and percentages of participants who had solicited local and systemic adverse events through day 7 after each vaccination and who had unsolicited adverse events through day 35.

We performed a per-protocol efficacy analysis in the population of participants who had been seronegative for SARS-CoV-2 at baseline and who had received both injections of NVX-CoV2373 or placebo as assigned, had no evidence of SARS-CoV-2 infection (by NAAT or anti-spike IgG analysis) within 7 days after the second injection (i.e., before day 28), and had no major protocol deviations affecting the primary efficacy outcome. A second per-protocol efficacy analysis population was defined in a similar fashion except that participants who were seropositive for SARS-CoV-2 at baseline could be included.

Vaccine efficacy (calculated as a percentage) was defined as (1–RR)×100, where RR is the relative risk of Covid-19 illness in the vaccine group as compared with the placebo group. The official, event-driven efficacy analysis targeted a minimum number of 23 end points (range, 23 to 50) to provide approximately 90% power to detect vaccine efficacy of 80% on the basis of an incidence of symptomatic Covid-19 of 2 to 6% in the placebo group. This analysis was performed at an overall one-sided type I error rate of 0.025 for the single primary efficacy end point. The relative risk and its confidence interval were estimated with the use of Poisson regression with robust error variance. Hypothesis testing of the primary efficacy end point was performed against the null hypothesis of vaccine efficacy of 0%. The success criterion required rejection of the null hypothesis to show a statistically significant vaccine efficacy.