Stig Östlund
tisdag, mars 31, 2020
The need to rapidly develop a vaccine against SARS-CoV-2 comes at a time of explosion in basic scientific understanding, including in areas such as genomics and structural biology, that is supporting a new era in vaccine development. Over the past decade, the scientific community and the vaccine industry have been asked to respond urgently to epidemics of H1N1 influenza, Ebola, Zika, and now SARS-CoV-2. An H1N1 influenza vaccine was developed relatively rapidly, largely because influenza-vaccine technology was well developed and key regulators had previously decided that vaccines made using egg- and cell-based platforms could be licensed under the rules used for a strain change. Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the Northern Hemisphere, it was available soon afterward as a stand-alone vaccine and was ultimately incorporated into commercially available seasonal influenza vaccines.
Vaccines for the severe acute respiratory syndrome (SARS), Ebola, and Zika did not follow a similar path. The SARS and Zika epidemics ended before vaccine development was complete, and federal funding agencies reallocated funds that had been committed to vaccine development, leaving manufacturers with financial losses and setting back other vaccine-development programs.
Development of an Ebola vaccine by the Public Health Agency of Canada had been on hold when the 2013–2016 Ebola outbreak began. The U.S. government provided funding to accelerate the vaccine’s development, which was ultimately transferred to Merck. The company continued development even when the outbreak ended, and stockpiles of investigational product were available for use in the recent outbreaks in the Democratic Republic of Congo. The vaccine received conditional marketing authorization from the European Medicines Authority and approval from the U.S. Food and Drug Administration at the end of 2019 and in several African countries thereafter. Some companies working on Ebola vaccines have received external support and invested their own funds to continue development. Even with successful development and licensure, however, the prospect that commercial markets will sustain multiple vaccines for which relatively few doses may need to be manufactured seems dim.
Reviews of the experience with H1N1 vaccine have stressed the need for novel development-and-manufacturing platforms that can be readily adapted to new pathogens. Vaccine and biotech companies have been investing heavily in such approaches, with support from the U.S. government and other funders. The National Institute of Allergy and Infectious Diseases has led an initiative to support early development of platforms and test them against “prototype pathogens” from various viral families.1
Our organization, the Coalition for Epidemic Preparedness Innovation (CEPI), an international nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom), is supporting development of vaccines against five epidemic pathogens on the World Health Organization (WHO) priority list. We aim to develop reserves of investigational vaccines for each pathogen after such vaccines have completed phase 2a trials, expecting that they will undergo clinical trials during future outbreaks. CEPI also supports development of platform technologies to prepare for “Disease X” — a newly emerging epidemic disease, such as Covid-19. An ideal platform would support development from viral sequencing to clinical trials in less than 16 weeks, demonstrate elicitation of consistent immune responses across pathogens, and be suitable for large-scale manufacturing using a pathogen-agnostic platform.
Multiple platforms are under development. Among those with the greatest potential for speed are DNA- and RNA-based platforms, followed by those for developing recombinant-subunit vaccines. RNA and DNA vaccines can be made quickly because they require no culture or fermentation, instead using synthetic processes. Developers’ and regulators’ experience with these platforms for personal oncology vaccines can facilitate rapid testing and release. There are no approved RNA vaccines to date, but RNA vaccines have entered clinical trials, and regulators have experience in reviewing clinical trial applications and with associated manufacturing of the vaccines.
Vaccine Platforms, Their Attributes, and the Status of Vaccine Candidates.
Use of next-generation sequencing and reverse genetics may also cut development time of more conventional vaccines during epidemics. The table lists major platform types and examples of SARS-CoV-2 vaccine types being developed on each. A more complete and continually updated list is available from the WHO.2
Even with novel platforms, SARS-CoV-2 vaccine development poses challenges. First, although the virus’s spike protein is a promising immunogen for protection, optimizing antigen design is critical to ensure optimal immune response. Debate continues over the best approach — for example, targeting the full-length protein or only the receptor-binding domain.
Second, preclinical experience with vaccine candidates for SARS and the Middle East respiratory syndrome (MERS) have raised concerns about exacerbating lung disease, either directly or as a result of antibody-dependent enhancement. Such an adverse effect may be associated with a type 2 helper T-cell (Th2) response. Hence, testing in a suitable animal model and rigorous safety monitoring in clinical trials will be critical. (It is still too early to define good animal models; rhesus macaques appear quite promising, as do hamsters and ferrets [unpublished data].) If adjuvants are required to generate a sufficient immune response or for dose sparing, those triggering a Th1 response and demonstrating a high neutralizing-antibody response are theoretically more likely to be protective and avoid the risk of immunopathology. However, data and careful regulatory review will be needed.
Third, although correlates of protection may be inferred from experience with SARS and MERS vaccines, they are not yet established. As with naturally acquired infection, the potential duration of immunity is unknown; similarly, whether single-dose vaccines will confer immunity is uncertain.
Difference between Traditional Vaccine Development and Development Using a Pandemic Paradigm.
Vaccine development is a lengthy, expensive process. Attrition is high, and it typically takes multiple candidates and many years to produce a licensed vaccine. Because of the cost and high failure rates, developers typically follow a linear sequence of steps, with multiple pauses for data analysis or manufacturing-process checks. Developing a vaccine quickly requires a new pandemic paradigm , with a fast start and many steps executed in parallel before confirming a successful outcome of another step, hence resulting in elevated financial risk. For example, for platforms with experience in humans, phase 1 clinical trials may be able to proceed in parallel with testing in animal models.
As soon as China announced that a novel coronavirus had been identified as the cause of the Wuhan outbreak, CEPI contacted its partners that were developing MERS vaccines or working on novel platforms. With the potential for further financial support, they and others began vaccine development as soon as the first gene sequence was posted, and development is proceeding quickly. Moderna’s mRNA-based SARS-CoV-2 candidate entered a phase 1 clinical trial on March 16, less than 10 weeks after the first genetic sequences were released; the first phase 1 trial with a nonreplicating vector-based vaccine has regulatory clearance to start phase 1 studies in China. Other phase 1 trials of nucleic acid vaccines are expected to start in April.
For some candidates, additional clinical trial material for phase 2 studies is being manufactured now; proceeding rapidly beyond phase 2 trials means manufacturing will need to be scaled up to commercial levels before substantial safety and immunogenicity data are available. Building manufacturing capacity can cost hundreds of millions of dollars. Furthermore, for novel platform technologies, most of which are unlicensed, large-scale manufacturing has never been done, so facilities capable of producing large quantities of product must be identified, technologies transferred, and manufacturing processes adapted, all without knowing if the vaccine candidate is viable.
It’s far from certain that these new platforms will be scalable or that existing capacity can produce sufficient quantities of vaccine fast enough. It’s therefore critical that vaccines also be developed using tried-and-true methods, even if they may take longer to enter clinical trials or to result in large numbers of doses.
Conducting clinical trials during a pandemic poses additional challenges. It’s difficult to predict where and when outbreaks will occur and to prepare trial sites to coincide with vaccine readiness for testing. In addition, if multiple vaccines are ready for testing in the second half of 2020, it will be important not to crowd sites or burden countries and their ethics and regulatory authorities with multiple trials, as happened with Ebola therapeutics during the 2013–2016 outbreak.
Moreover, in a high-mortality situation, populations may not accept randomized, controlled trials with placebo groups; although other approaches that address such concerns may be scientifically feasible, they’re typically not as fast, and the results can be harder to interpret.4 This problem can sometimes be overcome by comparing outcomes with early vaccination versus delayed vaccination, as in the “Ebola ça suffit!” trial. One possible way forward would be to test several vaccines simultaneously in an adaptive trial design using a single, shared control group, so that more participants would receive an active vaccine.5 This approach has advantages but can be logistically and statistically complex, and developers often avoid trials that may generate head-to-head comparative data.
CEPI, as a relatively new organization, had not established financial mechanisms and instruments to support development of pandemic vaccines and will need to raise additional funds to see SARS-CoV-2 vaccines through the development and scale-up manufacturing processes. Although as many as several million vaccine doses may become available as a by-product of development, in a pandemic situation, once vaccine candidates are proved safe and effective, doses must be manufactured in large quantities. Though some high-income countries may pay for development and manufacture with their own populations in mind, there’s no global entity responsible for financing or ordering vaccine manufacture. Discussions with global stakeholders about organizing and financing large-scale vaccine manufacturing, procurement, and delivery are under way.
Finally, pandemics will generate simultaneous demand for vaccines around the world. Clinical and serologic studies will be needed to confirm which populations remain at highest risk once vaccines are available and could form the basis for establishing a globally fair vaccine-allocation system. Some Group of Seven countries have already called for such a global system, whose planning must start while vaccine development proceeds.
Though it’s unlikely, if the pandemic appears to abruptly end before vaccines are ready, we should continue developing the most promising candidates to a point at which they can be stockpiled and ready for trials and emergency authorization should an outbreak recur. A global financing system that supports end-to-end development and large-scale manufacturing and deployment, ensures fair allocation, and protects private-sector partners from significant financial losses will be a critical component of future pandemic preparedness.
Disclosure forms provided by the authors are available at NEJM.org.
This article was published on March 30, 2020, at NEJM.org.
Kungsträdgåren (Stockholm) idag den 31 mars 2020. |
Vi är i dessa dagar inte i färd med att dö ut som art. Men kanske är vi i färd med att förändra oss som art.
Plötsligt är de dödsbringande utsläppen av koldioxid reducerade. Enligt WHO dör 4,6 miljoner människor varje år på grund av luftföroreningar. Nu går vi på sparlåga och inskränker oss till det nödvändigaste. Ordet frivillighet har blivit viktigare än ordet profit. Viruset har bokstavligen försett oss med ett ofrivilligt andningshål.
Vi upptäcker att vi ingår en planetarisk gemenskap. Men vi vill inte vara en del av den. Vi stänger gränserna för att stänga ute viruset, trots att varje expert på epidemier kan tala om för oss att fällda gränsbommar inte har någon effekt. Ett virus behöver inget visum. Psykologer däremot kan berätta att de stängda gränserna fungerar. Det är rädslans virus som hålls på avstånd från befolkningar som i decennier har fåtts att tro att allt ont kommer utifrån. /Carsten Jensen
Ungern är inte det enda exemplet på hur ledare använder coronapandemin som ett fönster för att tillskansa sig mer makt, rapporterar New York Times. I en genomgång nämner tidningen bland annat Israel där premiärminister Benjamin Netanyahu använt virusspridningen som förevändning för att stänga landets domstolar, vilket gjort att rättegången där han själv står anklagad för korruption skjutits på framtiden. I Thailand har premiärminister Prayut Chan-o-cha tagit sig rätten att censurera nyhetsmedier. Journalister som kritiserat regeringens hantering av virusutbrottet har blivit stämda. – Vi kan få en parallell pandemi av auktoritära och repressiva åtgärder, varnar FN:s Fionnuala Ní Aoláin i New York Times.
måndag, mars 30, 2020
Läkemedelsjätten Johnson & Johnson har slutit ett avtal med den amerikanska staten om att bygga upp kapacitet för att kunna tillverka en miljard doser av ett möjligt coronavaccin, skriver flera medier. Bolaget meddelar samtidigt att en vaccinkandidat ska börja testas på människor i september. Förhoppningen är att vaccinet i nödfall ska kunna användas så tidigt som i januari 2021. Det skulle förutsätta att myndigheter ger ett specialgodkännande. Aktien steg 4 procent på Wall Street efter nyheten på måndagen.
Det är lätt att känna stolthet över att leva i ett land där de flesta tar ansvar på egen hand – både för sin egen skull och av hänsyn till andra. Där vi känner tillit till varandra, och av goda skäl. Frivillighetslinjen har också gett resultat. Till följd av coronapandemin har två av tre svenskar avstått från att resa, träffa människor samt att resa kollektivt. (DN/Ipsos 27/3) Kalla dem de “folkvettiga”. Problemet är den minoritet – runt en tredjedel, enligt undersökningen – som tror att de står över detta. Som struntar i andra eller tror att de själva är odödliga. Uppenbarligen räcker inte en ”funderare”, ”folkvett” eller någons ”vädjan” för att de ska ändra beteende. Kanske ändrar de sig, kanske inte. Risken är att alla får betala priset för deras nonchalans, trots att en majoritet lagt om sina liv. Borde staten göra som i Norge, och peka med hela handen? Det återstår att se./SvD
Are smokers and tobacco users at higher risk of COVID-19 infection?
Smokers are likely to be more vulnerable to COVID-19 as the act of smoking means that fingers (and possibly contaminated cigarettes) are in contact with lips which increases the possibility of transmission of virus from hand to mouth. Smokers may also already have lung disease or reduced lung capacity which would greatly increase risk of serious illness.
Smoking products such as water pipes often involve the sharing of mouth pieces and hoses, which could facilitate the transmission of COVID-19 in communal and social settings.
Conditions that increase oxygen needs or reduce the ability of the body to use it properly will put patients at higher risk of serious lung conditions such as pneumonia.
Failed assassination attempt against U.S. President Ronald Reagan
In Washington, D.C., on this day (March 30) in 1981, barely two months after his inauguration as the 40th president of the United States, Ronald Reagan was shot and seriously wounded by would-be assassin John W. Hinckley, Jr. |
Inte bara svartvikare i Sundsvallstrakten utan även svartvikare i förskingringen
Hör av er. Vi kanske kan, (inte dumt särskilt nu i karantäntider) träffas på nätet. Kanske ordna en "nostalgi-ring", eller kommunicera med varandra på annat sätt.
Sänd mig era e-postadresser så kan jag tills vidare vara "samordnare" och låta alla få e-postadresserna.
Min adress:
stig.ostlund@hotmail.com
Firre i Halmstad, Kålle i Njurunda, Seved i Bosvedjan, Sten i Södertäljetrakten, Stig i,
jag tror, Örebro, Maj, Sara och Astrid i Sundsvallstrakten och alla
ni andra: hör av er !
Sänd mig era e-postadresser så kan jag tills vidare vara "samordnare" och låta alla få e-postadresserna.
Min adress:
stig.ostlund@hotmail.com
Firre i Halmstad, Kålle i Njurunda, Seved i Bosvedjan, Sten i Södertäljetrakten, Stig i,
jag tror, Örebro, Maj, Sara och Astrid i Sundsvallstrakten och alla
ni andra: hör av er !
Bergamo
The streets of Bergamo are empty. As in all of Italy, people can leave their homes only for food and medicines and work. The factories and shops and schools are closed. There is no more chatting on the corners or in the coffee bars.
But what won’t stop are the sirens.
While the world’s attention now shifts to its own centers of contagion, the sirens keep sounding. Like the air raid sirens of the Second World War, they are the ambulance sirens that many survivors of this war will remember. They blare louder as they get closer, coming to collect the parents and grandparents, the keepers of Italy’s memory.
The grandchildren wave from terraces, and spouses sit back on the corners of now empty beds. And then the sirens start again, becoming fainter as the ambulances drive away toward hospitals crammed with coronavirus patients.
“At this point, all you hear in Bergamo is sirens,” said Michela Travelli.
On March 7, her father, Claudio Travelli, 60, was driving a food delivery truck all around northern Italy. The next day, he developed a fever and flu-like symptoms. His wife had run a fever in recent days, and so he called his family doctor, who told him to take a common Italian fever reducer and rest up.
For much of the prior month, Italian officials had sent mixed messages about the virus.
On Feb. 19, some 40,000 people from Bergamo, a province of about a million people in the region of Lombardy, traveled 30 miles to Milan to watch a Champions League soccer game between Atalanta and the Spanish team Valencia. (The mayor of Bergamo, Giorgio Gori, this week called the match “a strong accelerator of contagion.”) Mr. Travelli and his wife didn’t take the threat of the virus seriously back then, their daughter said, “because it wasn’t sold as a grave thing.”
But Mr. Travelli could not shake his fever, and he got sicker.
On Friday, March 13, he felt unbearable pressure on his chest and suffered dry heaves. His temperature spiked and his family called an ambulance. An ambulance crew found her father with low levels of oxygen in his blood but, following the advice of Bergamo’s hospitals, recommended he stay home. “They said, ‘We have seen worse, and the hospitals are like the trenches of a war,’” Ms. Travelli said.
söndag, mars 29, 2020
M a r a d o n a rycker upp oss med kamerans hjälp
Maradona, enligt mig världens bäste fotbollsspelare någonsin fyller 60 år i år (oktober)
lördag, mars 28, 2020
Swedes are used to living alone, following rules and championing innovation. How much will these social norms help during the coronavirus crisis?
W
While people around the world are climbing the walls due to coronavirus lockdowns and social distancing, 21-year-old Swede Cajsa Wiking is unfazed by the prospect of spending time alone in her one-bedroom apartment in Uppsala.
“We are pretty good at staying home and aren't very social compared to other cultures...so that makes it easier for us,” she says. “I’m doing things like organising my closet, working out at home and I’m also reading more.”
More than half of all Swedish homes are, like Wiking’s, made up of one resident, the highest proportion in Europe, according to Eurostat figures. The most common age to move out from your parents’ place is between 18 and 19, compared to an EU average of 26.
Some experts believe that these living patterns might help stem the spread of coronavirus; in current hotspots for infections including Italy and Spain, it is – by contrast – much more common for large families to congregate under one roof.
“If you have a household with several generations, of course you are going to have a quick spread,” says Björn Olsen, a professor of infectious diseases at Uppsala University. “We have a lot of single people living in Stockholm, in the big cities in Sweden, and that could sort of slow the pace a little bit.”
Other commentators have pointed out the way many Swedes already behave when they’re outside in public spaces: it’s the norm to avoid sitting close to others on public transport and unusual to strike up small talk with strangers in shops or cafes.
“As for social distancing, Swedes already have that down and naturally gave each other tons of physical space way before the coronavirus pandemic hit,” says Lola Akinmade Åkerström, an author on Swedish culture.
Swedes are also used to “staying at home at the slightest inkling of a headache”, she adds, a sign that those with mild coronavirus symptoms are perhaps more likely to hunker down. This is partly because employers tend to encourage staff to take time off if they have coughs or colds to avoid sickness spreading within companies, while Sweden offers generous sick pay compared to many countries.
Collective responsibility
Sweden’s more formal efforts to tackle the coronavirus are controversial. Unlike in neighbouring European countries (including Denmark, which currently has a similar number of fatalities), public authorities are avoiding stricter measures and following a strategy of trying to slow down the spread of the virus in a calm and controlled way, while focusing on the protection of vulnerable groups.
This means schools for pupils under 16 remain open as well as most shops. Pubs and restaurants are still in business offering both table service and takeaway, although they’ve been asked to stop serving people at counters, and all events for over 50 people have been banned.
The government has asked people to follow authorities’ advice and take voluntary collective responsibility for slowing the spread of coronavirus. This includes working from home where possible, especially in the capital, self-isolating if you’re sick or over 70, and avoiding all non-essential travel.
“We who are adults need to be exactly that: adults. Not spread panic or rumours,” Prime Minister Stefan Löfven said recently in his first televised address to the nation since the start of the crisis. “No one is alone in this crisis, but each person has a heavy responsibility.”
The public’s response so far is largely indicative of the nation’s long-standing confidence in the state. A majority of Swedes watched and approved of his speech and believe the country can tackle the crisis well, according to a nationwide survey for Novus, a major polling company.
Stockholm’s public transport company SL says it saw passenger numbers fall by 50% on subway and commuter trains last week. Polls suggest three-quarters of Swedes are keeping at least a metre away from others at least some of the time. At least a third of Stockholmers are remote working, while Stockholm Business Region, funded by the city council, estimates that levels are well above 90% in the capital’s largest companies. Swedes also haven’t been panic buying as much as in other countries, although Lola Akinmade Åkerström remarks that “for one of the world’s top producers of toilet paper, it was surprising to witness the initial mad rush to stockpile toilet roll”.
But not all Swedes are taking the virus seriously. “I've still seen a lot of people [on social media] still hosting birthday parties with maybe 50 guests and going out clubbing, thinking nothing is the matter with that,” says Cajsa Wiking. “So I think definitely it is still a problem here, although it's different from other countries.”
“People are really keen to try and meet up, maybe because of the lack of social interaction you normally get through work,” adds Christoffer Carringer, a 29-year-old TV producer in Stockholm who says most people he knows are now working from home. He says his friends are “trying to be responsible” by going to the pub in groups of two or three and avoiding the most crowded places.
One mathematician has accused authorities of “playing Russian roulette” with the population by not introducing stricter rules, while several virologists including Professor Björn Olsen have called for Swedish authorities to follow other countries and “shut down everything that’s possible to shut down” as quickly as possible. Olsen disagrees with the Swedish Public Health Authority’s predictions that the population will quickly build up immunity, arguing this could take more than a year and is sceptical that the infection rate will level off during warmer summer months.
Akinmade Åkerström has also been critical of the current approach “considering the rise of infection cases and deaths around the world”. But she argues that strong support for authorities will help, should the country follow others into lockdown. “Most Swedes trust that the government has the best interest of society at heart and they will respond to stricter rules,” she says.
A connected population
History will be the judge of whether Sweden’s scientific and political policies hold up. But when it comes to day-to-day efforts to keep businesses and society functioning, Swedes’ working practices and passion for technology are two norms that are already playing out well during the corona crisis.
The Nordic nation has one of the most advanced digital economies in the EU and a strong background of innovation. More than two thirds of Swedes already work online from home at least some of the time, with around a third doing this on a daily or weekly basis, according to The Swedish Internet Foundation. Fast and widespread broadband works in tandem with social and company policies which champion flexible and remote working as part of a more balanced and gender-equal lifestyle. Nobody bats an eyelid if a parent clocks off in the early afternoon to collect a child from nursery; they’re trusted to catch up with their workload later.
This, according to Staffan Ingvarsson, CEO of Stockholm Business Region, has enabled a smooth transition to increased remote working. “Every company that has the possibility to do this, they are doing it, and it works,” he says.
Although keen to stress that coronavirus is still “dealing a really hard blow” to the economy, with bigger levels of layoffs than during the financial crisis, he also points to high levels of cross-industry collaboration that are helping Sweden to face new challenges brought by the crisis.
After thousands of staff from Scandinavian airline SAS were laid off, they were offered additional nursing training so they could support hospitals, thanks to funding from a private research foundation. Workers from truck-maker Scania are supporting a medical company to produce more respirators, and supermarkets have been actively targeting hotel and conference venue staff who’ve lost their jobs.
“It really warms my heart, all this innovation that is going on digitally,” says Ingvarsson, adding that he’s proud of how the Stockholm business community has been able to make so many big decisions together in the absence of physical meetings.
“Sweden is built on a history of collaboration and that shines through in times like this,” agrees Erik Engellau-Nilsson, CEO of Norrsken, a co-working space and investment fund that supports socially-minded entrepreneurs. The foundation recently set up an online platform where start-ups focused on solving problems connected to the coronavirus crisis can apply for funding. Engellau-Nilsson says he’s been “overwhelmed by the response and support from volunteers, initiatives, companies and partners”; initiatives already being profiled by the site include an e-learning company, an app offering free food deliveries for pensioners and a volunteering network.
The future?
What happens next will, of course, depend on how much the virus spreads. The Swedish Public Health Agency has warned that the worst is yet to come for the Nordic nation.
There are long-running concerns about whether hospitals are ready to cope with the potential demand for beds and intensive care equipment, while more recent debates have focused on how well authorities are communicating information. Some experts are calling for more specific instructions about how people should be living their lives. The Swedish Medical Association has expressed concerns that not enough has been done to inform residents who don’t speak Swedish, following a high proportion of deaths and infections in Stockholm’s Somali community, who are more at risk of sharing overcrowded housing.
And while some lone-living Swedes like Cajsa Wiking are confident they can keep their mood up by staying connected to friends and family via Facetime, others are worried about increased levels of loneliness should they end up housebound due to a lockdown.
“This could really affect how Swedes feel,” says Christoffer Carringer, who has recently started living alone for the first time. “Everyone is always screaming for sun and social interaction and attention this time each year after the long winter, so to be denied that, I think could have some sad side effects.” Akinmade Åkerström echoes this sentiment, saying: “For a society that thrives on being outdoors and in nature, that would be the most difficult part for Swedes to mentally deal with if a full lockdown goes into effect.”
Against this background, Sweden’s trust, technology and teamwork may well continue to be valuable assets for the country as things develop, but in times of crisis like this, nothing is certain.
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