Researchers Are Hatching a Promising Lower-Cost Coronavirus Vaccine

choi

The "hatching" in the NYT report is a pun.

Carl Zimmer, Researchers Are Hatching a Promising Lower-Cost Coronavirus Vaccine. New York Times, Apr 6, 2021, at page A6.
https://www.nytimes.com/2021/04/ ... lellan-vaccine.html
https://www.sandiegouniontribune ... coronavirus-vaccine

Quote:

(a) "A new vaccine for COVID-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines. And the new vaccine could be far easier to make.  Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients.

(b) "The first phase of clinical trials [on NVD-HXP-S] will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects.

(c) "But simply injecting coronavirus spike proteins [on coronavirus] into people is not the best way to vaccinate them. That is because spike proteins sometimes assume the wrong shape [postfusion], and prompt the immune system to make the wrong antibodies.  This insight emerged long before the COVID-19 pandemic. In 2015, another coronavirus [Middle East respiratory syndrome coronavirus (MERS-CoV)] appeared, causing a deadly form of pneumonia called Middle East respiratory syndrome. * * * Scientists call these two shapes the prefusion and postfusion forms of the spike [protein]. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don't stop it.

(d) "they ['McLellan and colleagues'] discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline.  The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. * * * The team filed a patent for its modified spike, but the world took little notice of the invention. MERS, although deadly, is not very contagious and proved to be a relatively minor threat; fewer than 1,000 people have died of MERS since it first emerged in humans.

(e) "All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-BioNTech — use the 2P spike.  Other vaccine-makers are using it as well. Novavax has had strong results with the 2P spike in clinical trials and is expected to apply to the Food and Drug Administration for emergency use authorization in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects to finish clinical trials later this year.

(f) "Two Prolines Are Good; Six Are Better [which is sectional heading:] * * * In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations.  The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. McLellan called the new spike HexaPro, in honor of its total of six prolines.  The structure of HexaPro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. McLellan hoped that its rugged design would make it potent in a vaccine.

(g) "Meanwhile, [Dr Bruce] Innes and his colleagues at PATH were looking for a way to increase the production of COVID-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own. With a Little Help From Eggs [which is sectional heading:] The first wave of authorized COVID-19 vaccines require specialized, costly ingredients to make. * * * The way influenza vaccines are made is a study in contrast. Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines.  The PATH team wondered if scientists could make a COVID-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make COVID-19 shots as well.

(h) "In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans. * * * [***] To develop an Ebola vaccine, for example, researchers added an Ebola gene to the Newcastle disease virus's own set of genes.  The scientists then inserted the engineered virus into chicken eggs. Because it is a bird virus, it multiplied quickly in the eggs. The researchers ended up with Newcastle disease viruses coated with Ebola proteins.  At Mount Sinai, the researchers set out to do the same thing * * * In a nod to both the Newcastle disease virus and the HexaPro spike, they called it NDV-HXP-S [NDV stands for New Castle Disease, and S, spike].

(i) "The potency [in animals; human trial is still underway, with phase I concerned about safety only] of the [NDV-HXP-S] vaccine brought an extra benefit: The researchers needed fewer viruses for an effective dose. A single egg may yield five to 10 doses of NDV-HXP-S, compared to one or two doses of influenza vaccines.

Note:
() Concerning quotation (c).
(i) On Mar 30 and 31, 2021 respectively, I published a posting titled "A Critical Patent to Produce Covid-19 Vaccines (I)" and (II).

In (I) the NYT report mainly attributed the 2P to the virologist Barney Graham of NIH.
(ii) This NYT article instead attributed this finding alone to "Jason McLellan, a structural biologist then at the Geisel School of Medicine at Dartmouth."  
(A) My Mar 31 posting "A Critical Patent to Produce Covid-19 Vaccines (II)" had Note (e) that cited a Proc Nat Acad Sci article about the 2P substitution (V1060P and L1061P) of S protein did have McLellan as the last author as well as one of the three corresponding authors. Whereas Barney S Graham was the third author from the last.
(B) Incidentally V and L are one letter abbreviations of amino acids valine and leucine, respectively.

(b) Quotation (f) talks about HexaPro.

Hsieh C-L et all (McLellan being last author), Structure-Based Design of Prefusion-Stabilized SARS-CoV-2 Spikes. Science, 369: 1501 (Sept 18, 2020)
https://science.sciencemag.org/content/369/6510/1501.long
("Substitutions of each category were identified that increased expression while maintaining the prefusion conformation (Fig 1 and Fig 2A). Overall, 26 of the 100 single-substitution variants had higher expression than S-2P (table S1)" )
(i) The S in "Table S1" stands for "supplemental," signifying the table is elsewhere ONLINE (not in this article, that is).
(ii) The authors tried on 100 variations of SARS-CoV-2 Spike protein, and decided HexaPro was the best in preserving the perfusion shape (of S protein). There is no need for you to read the article; view Fig 1 only, where the square in the left upper corner shows the four additional proline replacements: F817P, A892P, A899P and A942P.

F817P means the amino acid phenylalanine (whose one letter abbreviation is F, from the first two letter ph of the amino acid; it can not be P because P is assigned to proline by agreement) at the position of 817 (counting from the amino terminal of a protein) was replaced by another amino acid proline.

A892P means the 892nd amino acid alanine (one-letter abbreviation: A) is replaced by proline.  
(iii) Proline in Fig 1 is colored red throughout (the figure).
(iv) The other three squares in Fig 1 shows other modifications of the S protein that do not pan out. So you need not understand them.

(c) Quotation (g) mentions PATH.
(i) PATH (global health organization)
https://en.wikipedia.org/wiki/PATH_(global_health_organization)
("Its president and CEO is Nikolaj Gilbert [since December 2019] * * * Founded in 1977 with a focus on family planning, PATH soon broadened its purpose to work on a wide array of emerging and persistent global health issues")
(ii) Nikolaj Gilbert, March 2021 - February 2024. Board of Trustees, UNITAR (United Nations Institute for Training and Research)
https://unitar.org/about/unitar/ ... ees/nikolaj-gilbert  
("is president and chief executive officer of PATH. * * * Mr Gilbert is a Danish citizen and holds advanced degrees in business administration from Copenhagen Business School in Denmark and Ivey Business School in Canada.")
(iii) Tom Paulson, GLOBAL HEALTH PATH co-founder Gordon Perkin honored. Huamnosphere, Sep 3, 2010
https://www.humanosphere.org/glo ... don-perkin-honored/
("Dr Gordon Perkin, one of the co-founders of PATH and the Gates Foundation’s first director of global health, receives Canada’s highest honor today.  Perkin, who is Canadian but still allowed to reside in Seattle, is being awarded the Order of Canada for his many contributions to advancing global health.  He, Gordon Duncan and Richard Mahoney created PATH in 1977 (it was actually called something else before being renamed the Program for Appropriate Technology in Health [presently only the acronym is used, same as BP for the previous British Petroleum]) primarily to improve maternal and reproductive health in poor countries")

(d) Quotation (h) discusses "a vaccine, using a bird virus called Newcastle disease virus" hose genome is modified at least to include the gene for S protein, whose [virus's] propagation is in chicken eggs rather than in mammalian cells (in culture).
(i) In my Mar 10, 2021 posting titled "Why Johnson & Johnson's Covid-19 Vaccine Needs One Shot Only," paper No 5 contains Note (c) that stated,

"Johnson & Johnson does not announce the gene structure of its vaccine (trade secret?). So there is no way to comment further.  Johnson and Johnson does say it [adenovirus, whose genes are deleted (to reduce chance this virus would escape and multiply) and replaced with the gene for S protein] replies [sic; should be 'replicates'] on Janssen's AdVac and PER.C6 cell line. Hence I re-visit
Farson D et al, Development of Novel E1-Complementary Cells for Adenoviral Production Free of Replication-Competent Adenovirus. Molecular Therapy, 14: 305 (2006)"
(ii) AdVac® and PER.C6® are intellectual properties of Janssen, where AdVac is the adenovirus vector, and PER.C6 is a cell line derived from primary human embryonic retinal cell of an abortus.
(iii) I will deal with influenza virus and vaccine production in a separate posting.