New Coronavirus News from 6 Apr 2022

Medpage Today COVID Origins and EcoHealth Alliance; Malone Didn't Invent mRNA Vaccines LOOKING FOR TROUBLE [Medpage Today, 6 Apr 2022]

by Kristina Fiore

Welcome to the latest edition of Investigative Roundup, highlighting some of the best investigative reporting on healthcare each week.

The Nonprofit at the Center of the COVID Origin Debate
Vanity Fair's Katherine Eban details the evolution of the EcoHealth Alliance, the American non-profit with extensive ties to the Wuhan Institute of Virology that has fueled fires favoring a lab-leak origin for COVID-19.

The organization went from a struggling nonprofit focused on saving manatees (under the name Wildlife Trust) to winning multi-million-dollar federal grants to study pandemic prevention.

Its first big break came in 2009 when it won $18 million as part of a USAID pandemic prevention effort called PREDICT. But its leader, Peter Daszak, PhD, had been collaborating for years prior to that with Shi Zhengli, PhD, of the Wuhan Institute of Virology (WIV).

Daszak and Zhengli published their first paper together in 2005 -- on how horseshoe bats were a likely reservoir for SARS-like viruses. EcoHealth Alliance subcontracted $1.1 million of the PREDICT grant to WIV, Vanity Fair reported.

Eban details the work spawned by this alliance that has sparked several flash points in the SARS-CoV-2 origin debate. "Gain-of-function" research conducted in 2015 by Zhengli and collaborator Ralph Baric, PhD, of the University of North Carolina at Chapel Hill, involved the creation of two chimeric coronaviruses that were similar to the one that caused the 2002 SARS outbreak. One of those viruses was able to directly infect human cells, Vanity Fair reported.

In pursuit of securing future funding, EcoHealth Alliance also pitched the Defense Advanced Research Projects Agency (DARPA), which was seeking proposals for another pandemic prevention effort, called PREEMPT. The group wanted to examine SARS-like bat coronaviruses for furin cleavage sites and possibly insert new ones that would enable them to infect human cells. Vanity Fair noted that SARS-CoV-2 is notable for having a unique furin cleavage site that has led some scientists to consider whether the virus emerged from a lab. (DARPA rejected the proposal.)

Eban also details what appears to be concerted efforts by scientists to dismiss a lab-leak theory early in the pandemic.

On Feb. 1, 2020, NIAID Director Anthony Fauci, MD, emailed his deputy director Hugh Auchincloss, MD, with a subject line of "IMPORTANT," attaching the 2015 Baric and Zhengli paper. Later that day, Fauci joined a call, convened by Jeremy Farrar, director of the U.K.'s Wellcome Trust, that included a limited group of other top scientists including then-director of the NIH Francis Collins, MD, PhD, Kristian Andersen, PhD, and Robert Garry, PhD.

Over the next 4 days via email, the scientists scrutinized SARS-CoV-2's genetic sequence, paying special attention to the furin cleavage site. Initially, Andersen, Garry, and others found it "inconsistent with expectations from evolutionary theory." However, within a few days, four of the scientists who were on that call shared with Fauci the draft of a letter that argued a lab-leak theory was unlikely. It was published March 17, 2020 in Nature Medicine.

About a month before that, The Lancet published a statement from 26 scientists condemning "conspiracy theories" that COVID-19 doesn't have a natural origin. Daszak played a key role in organizing that paper, Vanity Fair reported.

Simon Wain-Hobson, PhD, of the Pasteur Institute in Paris, who has criticized gain-of-function research, told Vanity Fair that the group of scientists pushing the claim of natural origin "want to show that virology is not responsible [for causing the pandemic]. That is their agenda."

Malone Didn't Invent mRNA Vax
Robert Malone, MD, has become one of the loudest voices among physicians who spread COVID misinformation, buoyed by the claim he invented the mRNA vaccines -- but that claim is far from the truth, the New York Times reported.

The Times spent 2 days interviewing Malone at his 50-acre horse farm in Madison, Virginia -- about 2 hours southwest of Washington, D.C. -- where he was busy with appearances on conservative media, including Fox News and One America News.

He frequently uses his "inventor" status to question the safety of the mRNA vaccines, but COVID-19 experts, including three researchers who worked closely with Malone, told the Times his role was minimal at best.

Malone earned a medical degree from Northwestern University in 1991, and subsequently taught pathology at the University of California Davis and the University of Maryland over the next decade, before turning to biotech start-ups and consulting, the Times reported.

Malone did do work showing human cells could absorb RNA and produce proteins from it, as evidenced by a 1990 paper. But Malone was not the lead author, and at the time it wasn't known how to protect the genetic particles against immune system attack.

A co-author on that paper, Gyula Acsadi, MD, PhD, said none of the other authors would claim they had invented the mRNA vaccine, based on that paper.

"Some of his work was important, but that's a long way away from claiming to have invented the technology that underpins the vaccines as we use them today," Alastair McAlpine, MD, a pediatric infectious disease physician in Vancouver, told the Times.

The vaccines "are the result of hundreds of scientists all over the world, all combining to come together to form this vaccine," McAlpine said. "It was not one individual or the pioneering work of an individual person."

Valisure Wrongfully Investigated?
An FDA investigation into Valisure -- the upstart company that has detected carcinogens in several drugs and consumer products, leading to major recalls -- is dragging on and may be irrelevant, according to Consumer Reports.

About 7 months ago, the agency spent several weeks combing through Valisure's lab facilities and accused it of operating without proper regulatory approvals, Consumer Reports found.

The agency believes Valisure conducts tests for companies seeking FDA approval, but Valisure CEO David Light told Consumer Reports his company doesn't do that type of regulatory work.
Light added that the FDA has not communicated with him since that inspection.

Consumer Reports was able to obtain a copy of the 56-page inspection report, even though such reports are only supposed to be available when inspections are complete. (A FOIA officer subsequently realized the investigation was still open and asked Consumer Reports to destroy its copy.)

The inspection report held no evidence to support allegations that Valisure is doing preapproval testing for manufacturers, according to Consumer Reports.

Meanwhile, manufacturers of products that were recalled used the FDA investigation to undermine lawsuits brought by consumers who purchased goods implicated by Valisure's testing, the article states. It's not clear how manufacturers cited in the lawsuits found out about FDA's inspection of Valisure, as open investigations are confidential, Consumer Reports noted.

Valisure appeared on the scene in 2019 after discovering dimethylformamide in the blood pressure medication valsartan. Later that year, it revealed N-nitrosodimethylamine in the heartburn drug ranitidine. Last year, Valisure detected benzene in hand sanitizers, and then in several sunscreen sprays, and finally, in deodorants.

Americas at risk of further COVID-19 wave as cases surge in other regions, PAHO Director warns [Pan American Health Organization, 6 Apr 2022]

Washington D.C. 6 April 2022 (PAHO) – As cases of COVID-19 surge in Europe and East Asia due to Omicron BA.2, the Pan American Health Organization (PAHO) Director Carissa F. Etienne has urged countries to remain vigilant and urgently close vaccination gaps.

While COVID cases and deaths have dropped across much of the region, countries have reported more than 620,000 new cases each week. And in parts of North America and the Caribbean, where Omicron is becoming the predominant variant, new infections are beginning to rise.

With Omicron BA.2 already detected in 8.7% of sequences reported from South America, “time and time again, we’ve seen how the infection dynamics in Europe are mirrored here just a few weeks later,” the Director said in a media briefing today.

“We cannot ignore the risk of further COVID-19 surges,” she added. But we now “know what it takes to protect our people.”

However, with 240 million people in the Americas yet to receive a single shot of COVID-19 vaccine, vaccination gaps “will keep our region at risk during future waves.”

While more than 685 million people in the region have completed their COVID vaccination schedules, and 50 countries and territories have already begun to deliver booster doses, we must now “redouble our efforts to ensure that our vulnerable populations receive the doses they need,” as soon as possible, Dr. Etienne said.

The PAHO Director also urged countries to keep testing capacity in place “so we do not go into this next wave blind,” and have the full picture of Omicron BA.2 in the region.

“This means making tests easily accessible for everyone everywhere, to prevent new outbreaks and to prepare our health systems if cases surge,” she added.

Dr. Etienne also warned that some countries and territories have scaled back public health measures prematurely, highlighting that data “is our eyes and ears into this pandemic.”

“Just as we did before, we must adjust our strategies when cases rise, to save lives.”

With countries due to mark World Health Day on the 7th April under the theme “Our Planet, Our Health”, the PAHO Director also highlighted the urgent need for countries to work together towards a healthier, more sustainable future.

With an increase in temperatures, air pollution and extreme weather events, “it is undeniable that climate change has presented significant threats to our region’s health,” the Director said.
Health systems are also under threat as many hospitals were build in places vulnerable to floods, hurricanes, landslides and other extreme events.

“We are working to address this throughout the Region, but we all need to move faster,” added Dr. Etienne.

“Health system resilience is not just a necessity to overcome COVID, it is an investment for our future.”

SARS-CoV-2 transmission from human to free-roaming dogs during a severe COVID-19 outbreak in the Amazonian Region of Ecuador [News Medical, 6 Apr 2022]

By Dr. Liji Thomas

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that led to the devastating pandemic of coronavirus disease 2019 (COVID-19) has been found in remote jungles and humming urban centers alike. As efforts are on to stop the outbreak, using vaccines and public health interventions, the risk of spillover from wild mammals infected by the virus and living near humans is significant and may cause another epidemic as immunity wanes.

A new study shows how free-roaming village dogs in an Ecuadorian village within the Amazon jungle have been infected with the virus, presumably by the human hosts. The discovery of such infections and their ramifications are discussed in some detail.

Introduction
COVID-19 is primarily a zoonotic disease, presumed to have arisen from a bat coronavirus through an unidentified intermediate host. Now that the virus has spread widely throughout the world, it may spread in the reverse direction to animals; a phenomenon called zooanthroponosis. Dogs, cats, ferrets, hamsters, and such pet animals were screened for the infection early on.

This showed that dogs are relatively resistant to the virus compared to cats. However, numerous instances of dog and cat infections have been reported worldwide. Most such cases involved household dogs, ignoring the real problem of free-roaming dogs and cats that are found in large numbers in low- and middle-income countries, whether in city streets or in rural communities.

The current study, which appears in the journal One Health, deals with such a scenario.

What did the study show?
In this study, three free-roaming dogs in a small indigenous community that showed a high incidence of COVID-19 were infected with SARS-CoV-2, probably from humans. The isolation of the community means that it can be reached only from the air. The three dogs were fed collectively by the community.

The nasal and oral swabs from these three dogs, all adult males, were positive for the virus by the reverse transcriptase polymerase chain reaction (RT-PCR) test for viral ribonucleic acid (RNA). None of the dogs had symptomatic illness, but two or more viral nucleocapsid gene targets tested positive in all three. Two tested positive for the ORF1ab gene and one for the spike gene.

However, the cycle threshold (Ct) values were high in all three cases. Genomic sequencing could not be done, presumably because of the high Ct values.

The infection rate in the human community was 87%, with seven people having very high viral loads, over 108 copies/mL.

What are the implications?
In a heavily infected human community with free-roaming dogs, this initial report of human-to-dog transmission is the first anywhere in the world. Earlier, however, reports demonstrated that pet cats and dogs were readily infected with the virus by infected humans in the same or neighboring households.

The testing occurred as part of the surveillance program being carried out in indigenous communities in the Amazon region in Ecuador. Despite the absence of any symptoms of COVID-19, all three dogs in the village were infected. These dogs are part of the village’s food gathering and hunting activities and receive petting and food from all the community members indiscriminately.

The presence of seven heavily infected individuals within the community would account for the spread of the virus to the dogs, or at least to one of them, following which the dogs might well have spread it among themselves. The absence of the spike gene in two of the dogs could be due to the low viral loads, the same reason for the failure of genome sequencing.

Dogs have not been considered a likely source of SARS-CoV-2 transmission, but this is based on studies of pet animals from rich countries, where the number of free-roaming dogs is relatively low. In the different scenarios of developing and underdeveloped countries, the large number of dogs roaming the street could lead to such spread to other dogs, other companion animals, wild animals, and even humans.

The detection of the infection in these dogs is attributable to the sample collection simultaneous with the human outbreak. In earlier surveillance programs involving companion animals, samples from the latter were collected ten or more days after the first positive test in the animal owner.

The Amazon hosts a number of endangered species, and these may be further threatened by the rapid spread of COVID-19 among them. The Ecuadorian capuchin, which faces extinction in the near future under current circumstances, lives in the area that houses the community of this study.

Further research will be needed to elucidate the actual role of free-roaming and wild cats and dogs in the transmission of the virus and the infective period for animals following a diagnosis of COVID-19 in humans. This is crucial in understanding whether wild mammals can harbor the virus, leading to new forms of disease as well as creating unknown reservoirs of the virus.

Journal reference:
• Zambrano-Mila, M. et al. (2022) "SARS-CoV-2 infection in free roaming dogs from the Amazonian jungle", One Health, p. 100387. doi: 10.1016/j.onehlt.2022.100387. https://www.sciencedirect.com/science/article/pii/S2352771422000192

France reports over 200K Covid-19 cases as presidential polls approach [Business Standard, 6 Apr 2022]

France has reported 203,021 new Covid-19 cases in the past 24 hours, as the country prepares for the presidential elections on Sunday

France has reported 203,021 new Covid-19 cases in the past 24 hours, as the country prepares for the presidential elections on Sunday.

According to the French public health agency, 23,010 Covid-19 patients are currently hospitalised with 1,552 in intensive care. The agency also reported on Tuesday 140 additional Covid-19-related deaths in hospitals.

The application CovidTracker reported an increase in infections of 18.2 per cent in one week, with an average of 139,967 new daily cases reported between March 25 and 31, Xinhua news agency reported.

The application also reported an 8 per cent increase in the number of hospitalisations between March 25 and 31, with an increase of 3.6 per cent in intensive care admissions. Meanwhile, the number of daily deaths increased by 5.8 per cent.

According to the public health agency, 80.9 per cent of the French population has received at least one vaccine dose, and 79.5 per cent has been fully vaccinated.

France has lifted all Covid-19 restrictions. However, Morgane Bomsel, Research Director of the French National Center for Scientific Research, told French daily news BFMTV that "the pandemic is not over".

In the run-up to the presidential elections, the French Interior Ministry last week laid out health protocol for polling stations.

The vaccine pass or a negative Covid-19 test result will not be required to enter. However, while the wearing of masks and social distancing will not be mandatory, masks are recommended for the elderly, vulnerable and those who have tested positive for Covid-19.

COVID-19: Joint statement from ECDC and EMA on the administration of a fourth dose of mRNA vaccines [Europa.eu, 6 Apr 2022]

EMA’s COVID-19 task force (ETF) and the European Centre for Disease Prevention and Control (ECDC) have reviewed currently available studies and epidemiological data to provide a common position for EU/EEA countries on the current need and potential benefit of a fourth dose (second booster dose) of mRNA COVID-19 vaccines.

This statement is based on the currently available scientific evidence and, as such, is preliminary and may be subject to change as more data become available. This statement should not be interpreted as a regulatory decision in terms of changes to the product information. National recommendations regarding COVID-19 vaccines policies are made by National Immunisation Technical Advisory Groups.

Administration of a fourth dose of mRNA vaccines to immunocompromised individuals whose immune system may have mounted a suboptimal response to earlier vaccination is already recommended and should be part of current vaccination campaigns. There are currently no data on immunogenicity, safety or effectiveness of additional further doses in this population.
Additionally, in severely immunocompromised subjects, passive immunisation with monoclonal antibodies should be considered as an additional shield to protect against infection and disease.

The main source of empirical evidence on the potential public health impact of a fourth dose of mRNA vaccines as a second booster in immunocompetent individuals comes from data from Israel. These data indicate that a fourth dose of an mRNA vaccine given to immunocompetent individuals at least 4 months after the third dose is able to restore humoral immunity to the level seen after the third dose without raising any new safety concerns.
Immunogenicity data are available for a follow-up period of 3 weeks. No longer-term data are available on the duration of the achieved antibody levels however available data indicate that protection against Omicron infection may wane at a similar rate to that observed following the receipt of a third dose. Only preliminary data from Israel with respect to vaccine effectiveness against severe disease following a fourth dose are currently available.

There are currently no data with respect to a second booster dose of an mRNA vaccines in people who have received a primary series with another type of vaccine, e.g. a viral vector vaccine.

Although data on the rate of waning protection among the very elderly (adults above 80 years of age) following the first booster dose are still limited, due to the fragility of this population, the lower immune response to vaccination and the higher risk of severe COVID-19 a second booster could be administered. Data on safety and efficacy are only available for a fourth dose administered at least 4 months after a third dose, and this interval, together with local epidemiological data, should be taken into account when deciding on vaccination strategies.

In the context of continued high SARS-CoV-2 incidence, rates of severe outcomes and deaths remain low. For immunocompetent individuals between 60 and 80 years of age, there are currently no clear epidemiological signals from the European region of substantial waning of vaccine protection against severe COVID-19. Therefore there is no indication of an imminent need for a second booster dose in this population. However, continued close epidemiological and vaccine effectiveness monitoring is essential in order to rapidly detect signals indicating the emergence of an increasing risk of severe COVID-19 among vaccinated individuals. If such signals emerge, a fourth dose may be considered for adults between the ages of 60 and 80 years. Furthermore, local data on the epidemiological profile of severe COVID-19 cases may warrant a tailored use of a second booster dose in population groups identified as being at particular risk. If made available, vaccines adapted to better match recently circulating variants would be in principle preferable for additional boosters.

For immunocompetent individuals below 60 years of age, the administration of a second booster dose is not supported by the available data on continued level of vaccine protection against severe disease or death.

While seasonality is not yet established for SARS-COV-2, it is known that respiratory viruses tend to spread more consistently during the cold season. Therefore, plans for catch-up and re-vaccination campaigns should take this into account. In addition, in view of the possibility of new variants of concern (VOCs) emerging rapidly, the need to increase immunological breadth from available vaccines is a priority warranting the investigation of updated vaccine composition. However, it is still unclear when data on such updated vaccines will be available for a possible approval during the summer. Depending on whether waning protection against severe outcomes is observed in the coming months and on the evolving epidemiological situation, additional booster doses in anticipation of future waves or in advance of the next autumn/winter season may be needed in some or all age groups. Such additional doses will be of greatest value if administered closer to expected periods of increased viral circulation.

It must also be emphasized that, based on current evidence from longitudinal studies, routine surveillance and observational vaccine effectiveness studies, a primary course of vaccination remains the most efficient way to limit the disease burden and impact of COVID-19. COVID-19 vaccines continue to be very protective against severe disease, hospitalisation and death after completion of primary series and administration of the first booster dose. With vaccine uptake stagnating and in view of the significant variation in uptake across countries (only 63.5% of subjects aged 18 years and above in EU/EEA countries had received the first booster as of the end of March 2022), additional efforts are needed to increase vaccination uptake with a focus on the first booster dose as a public health priority.

ECDC and EMA will continue to closely follow vaccine effectiveness and epidemiological data, along with the progress in the development of adapted vaccines and will update advice accordingly. In addition, as more data are generated and submitted by marketing authorisation holders, these data may be reflected in the relevant product information where applicable.

The data and scientific evidence providing the basis for this statement are provided in the Annex.

Annex: Supporting rationale
Current epidemiological context
• Elevated COVID-19 incidence is resulting in a high proportion of reported hospitalisations and deaths among people with, but not necessarily due to, COVID-19. It is difficult to quantify this proportion which is likely to change over time with disease incidence. ECDC therefore considers ICU occupancy and ICU admissions to be the most reliable indicators of severity in the current context and the most stable over time.

• Many countries reported their highest case notification rates between January and February 2022 due to the highly transmissible Omicron variant of concern. Although this initial Omicron wave coincided with generally falling trends in all-age ICU admission rates since January 2022[1], some increases in early 2022 were observed in the number of older cases requiring admission to ICU, ventilation or ECMO, most notably among the 80+ age group.

• Despite the context of substantial co-circulation of influenza in most EU/EEA countries, all-cause mortality among age groups 65 and older and older adults (45 to 64) is currently declining[2].

• The EU/EEA has recently experienced an increase in COVID-19 cases among people aged 65 years and above, coinciding with the lifting of public health response measure and the more transmissible BA.2 Omicron sub-lineage becoming dominant. While ICU indicators are currently still low, the impact of this resurgence in the coming weeks will depend in part on the susceptibility of those who are infected to severe disease.

• Analysis of European COVID-19 surveillance data indicates that the highest rates of severe outcomes has been, and continues to be, among unvaccinated people. Within all age groups, occurrence of severe disease is extremely rare among those who have completed the primary vaccination course and/or received an additional booster dose.

• Although great progress has been achieved in uptake of COVID-19 vaccinations in the EU/EEA, there are significant variations in uptake across and within countries and population groups for the primary vaccination series and boosters. In the EU/EEA (as of end of March 2022) 83.3% of the adult (+18 years) population have received a full primary course of vaccination, 63.5% received a booster vaccination[3]. We also observe that vaccine uptake is stagnating. Therefore, continued efforts are needed to increase uptake in primary vaccination series and booster doses.

Vaccine effectiveness and impact in averted morbidity and mortality
• The rapid development and administration of COVID-19 vaccines has provided protection from severe disease and death globally. In 33 countries across the WHO European Region, an estimated 470,000 lives had been saved among those aged 60 years and over [4], as of November 2021[5].

• The number of cases of severe COVID-19 has been significantly decreased by the administration of a booster dose of COVID-19 vaccines after the primary vaccination.[6],[7]

• The effectiveness of current vaccines in preventing infections with the Omicron variant is lower than it was for previous variants,[8],[9] however COVID-19 vaccines continue to be highly effective in protecting all age groups against severe disease, hospitalisation and death.
Waning vaccine effectiveness of protection from severe disease
• Vaccine effectiveness (VE) against severe outcomes is high following the administration of a first booster dose, with estimates of around 80 to 90% protection against severe disease and hospitalisations up to 2 to 3 months after administration of a booster dose, with slight decreases after approximately 4 months.
o In elderly people (aged 70 years and older) in Finland before and after the emergence of the Omicron variant of concern, VE increased to 96% (95% CI, 95 to 97) 14 to 60 days after the third dose.[10] VE of other homologous and heterologous 3-dose series was similar. Protection against severe COVID-19 requiring ICU treatment was even better. Since 1 January 2022, the VE of Comirnaty was 91% (95% CI, 79 to 96) and 76% (95% CI, 56 to 86) 14 to 90 days and 91 to 180 days after the second dose, respectively, and 95% (95% CI, 94 to 97) 14 to 60 days after the third dose.

o In the Czech Republic, the VE of a Comirnaty booster against Omicron hospitalisation was 86% (95% CI, 84 to 89) 14 to 74 days after administration of the booster and reduced to 79% (95% CI, 74 to 82) after more than 75 days.[11] The VE against the need for oxygen therapy following a booster dose was 90% (95% CI, 87 to 92) 14 to 74 days after administration and reduced to 85% (95% CI, 80 to 88) after more than 75 days. The VE against the need for intensive care following a booster was 83% (95% CI, 75 to 89) 14 to 74 days after administration and 60% (95% CI, 37 to 74) after more than 75 days.

o A test-negative, case-control study from Qatar investigated vaccine effectiveness and the effectiveness of natural and hybrid immunity after the administration of a booster dose. The VE against hospitalisation and death was over 90% for both Comirnaty and Spikevax, around 7 weeks after the third dose. The authors concluded that hybrid immunity resulting from prior infection and recent booster vaccination confers the strongest protection against either Omicron subvariant (BA.1 and BA.2) and that vaccination enhances protection of those with a prior infection.[12]

o Among adults in the United States during the Omicron period, VE against hospitalisations was 91% during the first 2 months after a first booster, which decreased to 78% when more than 4 months passed since the first booster. [4]

o A case control mRNA vaccination study[13] performed in the United States focused exclusively on the most severe outcomes of COVID-19, including invasive mechanical ventilation (IMV) and death in adults aged 18 years and above. An overall high VE against IMV or in-hospital death of 90% was estimated. Sub-analysis indicated that while VE hardly decreases with age, it does reduce to a large extent depending on health status (from 92% in immunocompetent people to 74% in immunocompromised people), demonstrating that high levels of durable VE can be obtained by mRNA vaccination in healthy subjects.

o A nationwide cohort analysis from Denmark estimated the vaccine effectiveness against COVID-19-associated hospitalisation. The effectiveness after a booster dose of Cominarty was estimated to 88.8% (95% CI: 87.3 to 34 90.1%), declining to 79.0% (76.5 to 81.3%) in the fourth month, and 66.2 (61.1-70.7) at 4+ months after the booster dose. For Spikevax, the initial effectiveness was 90.2% (87.3 to 92.5%), declining to 83.6% (77.7 to 88.0%) in the fourth month, and 77.3 (63.1-86.1) at 4+ months.[14]

o Another study[15] showed that with the generally milder disease seen with Omicron, contamination of data on hospitalisations with incidental cases reduces VE estimates. With more precise VE estimates, high levels of booster VE against hospitalisation with the Omicron variant have been observed (up to 96%), in particular among older adults who are at greatest risk and against more severe outcomes. Nevertheless, there is evidence of limited waning of protection from 3-4 months after administration of a booster dose.

• Due to the recent exposure of large numbers of the population to the Omicron variant, hybrid immunity, gained from documented previous infection and receipt of a full-vaccination course, is likely to play an increasingly important role in protection at population level.[16],[17],[18] When combined with three vaccine doses, hybrid immunity provides additional population protection in the current context.

Current recommendations on booster doses in EU/EEA countries
• Many EU/EEA countries are currently recommending booster doses at a defined interval following primary vaccination, in light of evidence of waning protection over time.

• For immunocompromised individuals, all 30 EU/EEA countries recommend an additional primary dose as an extension of the primary vaccination course. Twenty countries also recommend a booster dose for immunocompromised individuals following the extended primary three-dose vaccination series (i.e. four doses).

• For the general population, all 30 countries also recommend first booster doses to different age groups due to waning protection. Half of the EU/EEA countries (15/30) recommend booster doses for all adults aged 18 years and over. Fifteen countries recommend boosters for adolescents (either to those over 12 years or those over 16 years).

• As of 5th April 2022, nine countries recommend a second booster dose (fourth dose) for different vulnerable population groups such as residents in long-term care facilities and the elderly, with different age cut-offs (Cyprus, Finland, France, Germany, Greece, Hungary, Ireland, The Netherlands and Sweden). The recommendations for a fourth dose for vulnerable people and certain at-risk groups aim to restore serological responses and overall vaccine efficacy.
The basis for the recommendations is the recorded waning over time of protection afforded by the third dose against infection and symptomatic disease, as well as local epidemiological considerations.[19],[20],[21]

Current recommendations on additional booster doses in other parts of the world
• The Australian Technical Advisory Group on Immunization made recommendations on 25 March 2022 on a fourth COVID-19 vaccine dose to increase vaccine protection before their winter season for some groups, including adults aged 65 and older, residents in long-term care facilities and the severely immunocompromised. On 29 March 2022, the United States Food and Drug Administration (FDA) authorised the use of a second booster dose of either the Pfizer-BioNTech COVID-19 vaccine (Comirnaty in the EU) or the Moderna COVID-19 vaccine (Spikevax in the EU) for individuals 50 years of age and older at least 4 months after receipt of a first booster dose. Following this authorisation, the US Centers for Disease Control and Prevention (CDC) updated their recommendations to allow certain immunocompromised individuals and people over the age of 50 who received an initial booster at least 4 months earlier to be eligible for another mRNA booster.

Effectiveness and safety of a second booster vaccination with mRNA vaccines
• The vaccine effectiveness of a second booster dose has been studied mainly in subpopulations considered to be at higher risk for severe COVID-19. Data are still limited, and all data pertain to the Omicron variant. Effectiveness in preventing infection is observed for a few weeks after the administration of the fourth dose but decreases quickly over time. Early data from Israel indicate that the risk of severe infection and/or death due to COVID-19 is decreased for up to 10 weeks after the administration of a fourth dose as compared to those receiving only the third dose, albeit in populations already experiencing very low levels of severe outcomes and thus providing minimal absolute reduction in severe outcomes. The maximum duration of this protection is not yet known due to short follow-up times in the studies available.

o In an open-label, nonrandomized clinical study[22] conducted during the Omicron period in Israel, the immunogenicity, safety and efficacy of a fourth dose of either Comirnaty or Spikevax was evaluated in healthcare workers when administered at least 4 months after the third dose of Comirnaty. All participants were actively screened for SARS-CoV-2 infection on a weekly basis. The data from this small interventional study showed that administration of a fourth dose does not reveal new serious adverse events and that it restores humoral responses to the highest level seen post-third dose. Only subjects expected to be at higher risk of infection were enrolled in the study (whose IgG antibody levels are below the 40-percentile). Breakthrough infections, nearly all asymptomatic, were very common and VE against SARS-COV-2 infection was not established (point estimates 10-30%, and non-statistically significant). There are no data to show that a fourth vaccination may be of benefit in healthy younger adults.

o During the Omicron period, real-world evidence collected from electronic medical records in Israel and summarized in a pre-print study showed that subjects aged 60 to 100 years, including patients with comorbidities, were significantly less likely to die from COVID-19 if they received a second booster compared to those immunized with only 3 doses at least four months earlier. The absolute risk reduction conferred by the fourth dose was 0.07% in circumstances of high circulation of Omicron variant.[23] Similarly, a preprint for a retrospective test-negative case-control study in Israel showed that subjects 60 years of age or older who received a second booster was 73% effective in preventing severe breakthrough COVID-19 (defined as COVID-19-related hospitalisation or death) during at least 9 weeks of follow-up compared with those who received only the first booster, although severe disease was a rare event (<1%) in both groups and relative effectiveness appeared to wane somewhat over time in the fourth dose group relative to the third dose group.[24] Both studies adjusted their results for differences between the groups with regards to age, gender, socioeconomic status, underlying comorbidities and calendar week of testing.

o Another study among 1.2 million Israelis aged 60 and older estimated vaccine effectiveness of the fourth dose of Comirnaty against SARS-CoV-2 infection and severe illness due to COVID-19.[25] The results showed a 2-times lower rate of confirmed infection and a 3.5-times lower rate of severe COVID-19 in adults in this age group in the fourth week after receiving a fourth dose compared to adults who received a third dose more than four months before. Protection against confirmed infection waned in the later weeks, whereas protection against severe illness did not wane during the short follow period of 6 weeks after receipt of the fourth dose.

• The waning of protection from a second booster dose has not yet been sufficiently studied due to the limited follow-up period. Existing studies are observational and, thus, unavoidably present limitations, including residual confounding factors. Several of the studies are still awaiting peer review. Although studies make adjustments for calendar time, age, and other potential confounders, it cannot be guaranteed that there are no remaining differences between the groups that can influence the VE estimate.

• Despite the relatively small size of the safety database, no major safety issues have emerged following administration of the second booster dose, a finding which is consistent across studies. The EMA will continue monitoring the safety of the second booster closely.

Implementation considerations
• As data on adapted vaccines will be available in the near future and possibly lead to the authorisations of adapted vaccines later on in the year, vaccination campaigns should take into account the impact of repeated booster doses on vaccine acceptance and uptake in the general population. The offer of a fourth dose should be promoted on the basis of an understanding of: (a) public concerns and expectations regarding the vaccines and (b) people’s perceptions and concerns about the disease itself. Behavioural research can offer important insights into vaccination ‘fatigue’ and the low risk perception of the disease among many people today, and thereby providing direction to vaccination campaigns.
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[1] ECDC. https://www.ecdc.europa.eu/en/covid-19/country-overviews
[2] EuroMOMO. https://www.euromomo.eu/bulletins/2022-12/
[3] ECDC Vaccine Tracker
[4] Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021| Eurosurveillance
[5] Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021| Eurosurveillance
[6] Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel | NEJM
[7] BNT162b2 Vaccine Booster and Mortality Due to Covid-19 | NEJM
[8] Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta variants| Nature Medicine
[9] Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study| medrxiv
[10] High vaccine effectiveness against severe COVID-19 in the elderly in Finland before and after emergence of Omicron—medrxiv.org
[11] Protection by vaccines and previous infection against the Omicron variant of SARS-CoV-2—medrxiv.org
[12] Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar
[13] Effectiveness of mRNA Vaccination in Preventing COVID-19–Associated Invasive Mechanical Ventilation and Death — United States, March 2021–January 2022 (cdc.gov)
[14] Vaccine effectiveness against infection and COVID-19-associated hospitalisation with the Omicron (B.1.1.529) variant after vaccination with the BNT162b2 or mRNA-1273 vaccine: A nationwide Danish cohort study
[15] Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation: test negative case-control study (khub.net)
[16] Protection against SARS-CoV-2 after Covid-19 Vaccination and Previous Infection | NEJM
[17] Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden - The Lancet Infectious Diseases
[18] Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study - The Lancet Infectious Diseases
[19] Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study - ScienceDirect
[20] Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022 (cdc.gov)
[21] COVID-19 vaccine surveillance report - week 9 (publishing.service.gov.uk)
[22] Efficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron | NEJM
[23]Second Booster Vaccine and Covid-19 Mortality in Adults 60 to 100 Years Old | Research Square
[24] Relative Effectiveness of Four Doses Compared to Three Doses of the BNT162b2 Vaccine In Israel | medRxiv
[25] Protection by a Fourth Dose of BNT162b2 against Omicron in Israel | NEJM

ECDC and EMA issue advice on fourth doses of mRNA COVID-19 vaccines | European Medicines Agency [European Medicines Agency, 6 Apr 2022]

The European Centre for Disease Prevention and Control (ECDC) and EMA’s COVID-19 task force (ETF) have concluded that it is too early to consider using a fourth dose of mRNA COVID-19 vaccines (Pfizer’s Comirnaty and Moderna’s Spikevax) in the general population.

However, both agencies agreed that a fourth dose (or second booster) can be given to adults 80 years of age and above after reviewing data on the higher risk of severe COVID-19 in this age group and the protection provided by a fourth dose.

ECDC and EMA also noted that there is currently no clear evidence in the EU that vaccine protection against severe disease is waning substantially in adults with normal immune systems aged 60 to 79 years and thus no clear evidence to support the immediate use of a fourth dose.

Authorities will continue to monitor data to determine if there is an increasing risk of severe illness among those who are vaccinated.

If the current epidemiological situation changes and new signals emerge, it may become necessary to consider a fourth dose in this age group. In the meantime, national authorities will also consider local data in deciding whether to use a fourth dose in those people at higher risk.

For adults below 60 years of age with normal immune systems, there is currently no conclusive evidence that vaccine protection against severe disease is waning or that there is an added value of a fourth dose.

As re-vaccination campaigns could start in the autumn, authorities will consider the best timing for additional doses, possibly taking advantage of updated vaccines.

So far, no safety concerns have emerged from the studies on additional boosters.

Vaccination against COVID-19 remains the most effective way to prevent severe illness during the current pandemic, including severe illness caused by the Omicron variant.

ECDC and EMA urge EU citizens to complete their schedules for both initial and booster vaccinations in line with national recommendations. As of the end of March 2022, 83% of adults had received full initial vaccinations and only 64% had received a booster dose.

What the evidence says about second booster doses
Evidence on the effects of a fourth dose comes largely from Israel, where data indicate that a second booster given at least 4 months after first booster restores antibody levels without raising any new safety concerns. Data also suggest that a second booster provides additional protection against severe disease, although the duration of the benefits is not yet known and the evidence is still limited.

Details of the evidence assessed by both agencies is available in the joint ECDC-EMA statement on second boosters.

Other factors to be considered in vaccination campaigns
National authorities in the EU make final decisions on the roll-out of vaccines, including booster doses, taking into account factors such as the spread of infection, the effects of COVID-19 in different populations and the emergence of new variants.

ECDC and EMA will continue to review available evidence on the effectiveness of COVID-19 vaccines and update their recommendations accordingly. EMA will also consider all emerging data on the safety and effectiveness of booster doses with a view to updating the product information for COVID-19 vaccines where applicable.

Scientists divided on need for 4th Covid shot after FDA quietly approved another round of boosters [CNBC, 6 Apr 2022]

by Spencer Kimball

Leading U.S. scientists and physicians worry that the FDA and CDC are moving too fast in approving a fourth round of Covid shots, with little public debate that gives the vaccine makers too big a role in setting the pace with which the doses are distributed across the nation.

The top U.S. public health agencies last week endorsed a fourth Covid shot for older adults without holding public meetings, drawing criticism from leading vaccine experts who believe federal health officials haven’t provided enough transparency about the reasons for the decision.

The authorization of a fourth dose for adults age 50 and older comes as the scientific community is divided over whether the data is sufficient to support another round of boosters, and whether authorizing additional shots is a sustainable public health policy, especially since protection against infection simply wears off over time. There is a debate over whether the goal of the vaccines is to prevent severe illness, which they’ve largely achieved, or infection as well — a more challenging proposition.

The Food and Drug Administration authorized a second booster shot for people age 50 and older last week, and the Centers for Disease Control and Prevention quickly backed their distribution hours later based on data from Israel, which rolled out fourth doses months ago.
Dr. Peter Marks, who heads the FDA office responsible for vaccine safety and efficacy, said shortly after the decision that another round of boosters will likely be needed in the fall.
Rapid approval

The rapid regulatory clearance of fourth shots for older adults came just weeks after Pfizer and Moderna asked the FDA to permit them. Several FDA and CDC committee members as well as other leading experts said Pfizer and Moderna are playing too large a role in setting the agenda around U.S. vaccine policy by announcing the need for fourth doses and possibly a variant-specific vaccine before the public health agencies have made any recommendations.

Moderna CEO Stephane Bancel said during a January interview with Goldman Sachs that fourth doses would be needed in the fall as the protective antibodies from the shots wane over time. Pfizer CEO Albert Bourla told CNBC in early March, before the company filed its request with the FDA, that there’s a need for a fourth dose though he said the regulators would ultimately come to their own conclusion.

“I just think it’s sort of booster mania. I think the companies are frankly acting like public health agencies,” said Dr. Paul Offit, a member of the FDA committee and one of the nation’s top vaccine experts. Offit said the CDC, which has the final say on vaccine recommendations, needs to develop a clear national strategy to reduce public confusion about what it means to be fully vaccinated at this stage in the Covid pandemic.

Michael Osterholm, a leading epidemiologist, said repeated boosting is not a sustainable public health strategy because of the challenge posed by waning immunity against infection. “We’re not gonna be able to boost our way out of this,” said Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

Call for more transparency
The FDA and CDC vaccine advisory panels weigh safety and efficacy data before making recommendations to top federal health officials on the best path forward. Though the recommendations are nonbinding, the meetings provide an open forum where the public can listen to the nation’s top health experts debate the pros and cons of vaccine policy, and often even participate by phoning in to voice their views.

The FDA’s Vaccines and Related Biological Products Advisory Committee is meeting Wednesday to debate the future of boosters. However, it will not vote on any specific recommendations, according to the FDA. The CDC’s Advisory Committee on Immunization Practices did not meet before CDC Director Dr. Rochelle Walensky signed off on the fourth shots for older adults last week.

“It’s just sort of fait accompli,” Offit said. “I feel that we’re in a time, this sort of Covid exceptionalism, where we don’t do things the way we normally do it, which is that the science precedes the recommendation. Here, it’s the other way around,” he said.

Offit said that the FDA is effectively asking the public to believe that the data supports a fourth dose by providing sufficient protection against serious illness. He said the American public benefits from hearing an open discussion about vaccine decisions, particularly at a time when many people are not taking advantage of the third dose. Offit is an infectious disease expert at Children’s Hospital Philadelphia and a co-inventor of a rotavirus vaccine.

Marks, during a call with reporters last week, said the FDA did not call a committee meeting because the decision was “relatively straightforward.” He said data from Israel suggested a fourth dose can reduce the risk of hospitalization and death in older adults. The CDC, in a statement to CNBC, said the fourth dose was an incremental change that did not need to go before its committee.

Dr. William Schaffner, a nonvoting member of ACIP, disagreed that the CDC recommendation was an incremental change. Schaffner said clearing fourth doses for older adults is a big decision that would have benefited from a meeting of outside advisors to provide the public with transparency.

“I think to have this decision made in-house behind closed doors without having the transparency of a full debate that a regularly called ACIP meeting would have provided – I think that’s unfortunate,” said Schaffner, an infectious disease expert at Vanderbilt University Medical Center.

Dr. James Hildreth, who is attending the FDA committee’s Wednesday meeting as a temporary member, noted that the drug regulator wasn’t required to call a public meeting before authorizing the shots, and the agency has seasoned experts who can determine if there is evidence to support a new authorization. However, Hildreth said moving forward without a recommendation from outside experts fuels the perception that industry is playing too big a role in the nation’s vaccine strategy.

“When the FDA makes a decision like that without calling together an outside group of experts, it just adds to the optics of the pharmaceutical companies having an impact on decisions that are being made,” said Hildreth, president of Meharry Medical College in Nashville, Tennessee. Meharry is a clinical trial site for Novavax’s vaccine as well as Moderna’s shots for younger children.

‘Diminishing returns’
While some health experts believe the central purposes of the vaccines is to prevent severe illness, others think it is important to also stop infections from the virus. The protection provided by the Pfizer and Moderna vaccines against infection has declined substantially over time, particularly in the context of omicron, which has numerous mutations that give it an enhanced capability to cause breakthrough infections and mild illness. However, the vaccines are still providing substantial protection against severe illness.

“If you’ve gotten a mild illness after you’ve been vaccinated, you’ve won — that’s it. You’ve been prevented from having serious illness, which is the stated goal of this vaccine,” said Offit, who believes three doses were necessary for the elderly and four for the people with weak immune systems, but is skeptical of the need for additional shots right now.

But if the goal is also to prevent infection, that means, at least for now, booster shots are the only available tool to increase antibodies until a longer-lasting vaccine is available. The problem is that the vaccines eventually run into diminishing returns, according John Moore, a professor of microbiology and immunology at Weill Cornell Medical College. Moore said a three-dose regimen is fairly standard with vaccines to help boost the immune system to its peak response. A fourth shot, however, begins to hit a ceiling — at least in terms of protecting younger people against infection.

The Israeli Health Ministry and scientists at Sheba Medical Center found that a fourth dose does restore antibodies that waned off after a third dose among health-care workers ages 18 and older, but it provided little protection against infection. Pfizer cited that study, which has not undergone peer-review, among others in its statement on the FDA authorization, focusing on the increased antibodies without highlighting the issues with breakthrough infections.

Different age, different needs
Dr. Peter Hotez, a vaccine expert at the Baylor College of Medicine in Houston, strongly supports a fourth dose for older adults, pointing to a CDC study from February that found the third shot’s effectiveness against hospitalization dropped from 91% to 78% after four months.

Pfizer, in its public statements on the fourth dose, cited a separate Israeli study that found a fourth dose reduced mortality by 78% in people ages 60 and over. The study from Ben Gurion University and Clalit Health Services, which has not undergone peer-review, analyzed the medical records of more than 500,000 people.

’We continue to collect and assess all available data and remain in open dialogue with regulators and health authorities to help inform a Covid-19 vaccine strategy as the virus evolves,” Pfizer said in a statement to CNBC.

While the Ben Gurion study may point in the direction of a benefit for older adults at the moment, the evidence for boosting younger adults again is scant as the U.S. considers lowering the eligibility for fourth doses sometime later in the year.

Dr. Gili Regev-Yochay and her team of scientists at Sheba said a fourth dose “may only have marginal benefits” for younger people, according to a letter published in the New England Journal of Medicine. While Pfizer originally filed for adults age 65 and older, Moderna asked the FDA authorize a fourth dose for ages 18 and older. Moore called Moderna’s filing “aggressive,” arguing that it didn’t distinguish between the needs of the elderly, who may benefit from an additional dose, compared with younger adults where the data is less convincing.

Moderna CEO Bancel told CNBC last month that the company wanted to give the FDA flexibility to decide which age group would benefit most from a fourth shot right now.
Moderna, in its public statements on its application for a fourth dose, pointed to data from Israel but didn’t cite specific studies.

Though Hotez supports a fourth dose for older adults, he said the FDA and the CDC have not done an effective job at communicating whether the goal of the vaccines is to prevent severe illness, infection or both, and the vaccines makers have filled that void with statements on data from their clinical trials and lab studies. Hotez and a team of scientists in Texas developed a Covid vaccine, Corbevax, based on traditional protein-based technology that has received authorization in India.

Hotez also expressed frustration that the U.S. relies heavily on data from abroad, particularly Israel and the U.K. Offit also questioned why the U.S. is relying on data from countries that are smaller than the U.S. and have different demographic backgrounds.

Long-term strategy needed
Hildreth said the U.S. should put off additional booster doses as long as the public health situation allows so the nation can more clearly define how it measures protection against the virus and develop a long-term strategy to achieve that end. He said if the public is asked to get boosted every several months, many people will simply stop listening.

“We don’t know a specific measure we can do to say whether or not a person is truly protected, and whether or that’s the same with everybody,” said Hildreth. For example, there’s no clear measure of whether a certain level of antibodies is sufficient to protect people, he said.

Beyond vaccination with the current vaccines, Pfizer and Moderna are developing shots that target omicron as well as other variants. Dr. Arnold Monto, who is chairing the FDA’s committee meeting on booster strategy Wednesday, said public health authorities need to develop a consensus about what goes into the vaccines moving forward. Monto said collaboration between the vaccine makers and the government is crucial, but industry has started playing a larger public role in decisions about about what kind of vaccines should be developed to target specific Covid variants.

“Industry has a double-headed goal. They are trying to do public good like we all are. They also have stockholders, and we need to be sure that the public health good is kept mind,” Monto said.