It was a beautiful sunny and windy 60F here today in stony brook Long island. I typically only write in for TWIP (I’m the one who likes to send pictures and videos of fish parasites) but I am emailing you because I am the one who corrected Dickson on his not wrong but not right information concerning iron in the oceans. To clarify, Dickson is right that Iron is limiting to plankton growth in many areas of the ocean, but the point I made last time was that iron is only limiting in certain areas of the ocean, specifically the open ocean. So areas such as the coast are not typically limited by iron due to the close proximity to land which is a major source of iron. As you move away from the coast iron will become more limiting, but these areas can also be limited by other nutrients such as nitrogen and phosphorus. Areas that are most depleted in iron are the high nutrient low chlorophyll (HNLC) zones such as the southern ocean as these areas have large amount of upwelling bringing up nutrients (nitrogen) but are relatively removed from the coast so they are limited by iron.These HNLC zones are actually where the iron fertilization experiments took place. So I didn’t say Dickson was crazy, but that he was slightly incorrect in saying that all the ocean is limited by iron. Furthermore Dickson mentioned harmful algae blooms (HABs) are limited by iron, but because HABs are defined by the damage they do, specifically they damage in relation to anthropogenic resources (fisheries, water resources etc.) they are typically on the coasts. So HABs are rarely limited by iron, but excess nutrients, primarily nitrogen, from fertilizer and waste water run off typically cause these blooms. Sorry to be nit picky but as HABs become ever more prevalent with climate change and such it is important to clarify these details.
Additionally I would like to add to Dickson’s comments about William Campbell with a short story. I met William Campbell at the Helminthological Society of Washington meeting directly after he had received his Nobel Prize. he was arguably the most delightful scientist I have yet to meet. At a small meeting (<100 ppl) he made time to talk to every undergraduate (which I was at the time) even though he had just won the most prestigious award a scientist could. Furthermore upon talking to a fellow lab mate who was interested in veterinary parasitology, he offered to send one of his own personal textbooks from his library to a sophomore he had just met because it could be a valuable resource for her. truly a nice man, who has done wonders for this world, and I look forward to hearing the TWIP heros section that I’m sure you will write about him.
Anyways, Loved the episode, thought it was one of the most interesting i’ve heard yet.
Dear League of Extraordinary Virologists,
It’s hard to believe that the fascinating podcast I started listening to in 2008 is now on episode 568, and we all seem to be just as young and sassy as back then. It must be due to better life through virology.
I remember being impressed with your early description of recombinant flu vaccines as having the ability to produce a protein which could not be accomplished through egg production. The ability to produce vaccine in a shorter time, closer to flu season, also had the obvious potential to address the most recent strains. I believe this discussion was prior to clinical trials.
Can you give us a timely update on the advantages of Flublok which has become commercially available. Breadth and level of protection, age appropriateness, etc.
Thanks for keeping us young and healthy,
Frank in Sausalito
Hi Professors TWiV,
So for the first time ever, I got the flu. It has, frankly, sucked and I hope I never get it again.
I got it four days after my annual flu shot. Now, I’m a devoted nurse and listener to TWiV so I know that the flu shot didn’t give me the flu. BUT, one of my good buddies, a pharmacist to boot, has decided that it was the shot that gave me the flu and furthermore, he’s not going to get vaccinated this year against the flu. I’m so irritated I could spit, but that will probably trigger another gigantic coughing fit.
I’m going to nag him (I’m sure that will go great! #sarcasm) so I have a couple of highly speculative questions, if you’d be so kind as to indulge me.
First, what are the odds that a flu vaccine would be released with live virus? (In the shot, of course, not the live attenuated intranasal vaccine) second, IF, in the presumably highly unlikely scenario that the shot contained infectious virus, is there any possible way the virus can make its way over to the airway tissues from the deltoid and start infecting? I don’t know viruses well enough to know, but it seems really unlikely. And of course, with basic stats, we know that the possibility of two unlikely events is markedly higher than a single unlikely event.
I hope these questions aren’t too dumb. Please feel free to ignore this if it’s just too silly.
As always, thank you for a terrific podcast that I never miss. I appreciate all the time you you put into it, your camaraderie, the groan-worthy puns, and, as always the science.
Seattle where the weather is happening but I have not been outside in days because of the dumb flu 🙁
Get vaccinated – tetanus
TETANUS – USA: (OR) UNVACCINATED CHILD, 2017
A ProMED-mail post
Date: Fri 8 Mar 2019
Source: CDC. MMWR Morb Mortal Wkly Rep 2019; 68(9); 231-2 [edited] <Caution-https://www.cdc.gov/mmwr/volumes/68/wr/mm6809a3.htm?s_cid=mm6809a3_w>
ref: Guzman-Cottrill JA, Lancioni C, Eriksson C, et al. Notes from the
field: Tetanus in an unvaccinated child — Oregon, 2017. MMWR Morb Mortal Wkly Rep 2019; 68: 231-2.
Tetanus is an acute neuromuscular disease caused by the bacterium _Clostridium tetani_. Bacterial spores found in soil can enter the body through skin disruption, with subsequent onset of clinical illness ranging from 3 to 21 days (usually within 8 days). In 2017, a boy aged 6 years who had received no immunizations sustained a forehead laceration while playing outdoors on a farm; the wound was cleaned and sutured at home. 6 days later, he had episodes of crying, jaw clenching, and involuntary upper extremity muscle spasms, followed by arching of the neck and back (opisthotonus) and generalized spasticity. Later that day, at the onset of breathing difficulty, the parents contacted emergency medical services, who air-transported him directly to a tertiary pediatric medical center. The boy subsequently received a diagnosis of tetanus and required approximately 8 weeks of inpatient care, followed by rehabilitation care, before he was able to resume normal activities.
Upon hospital arrival, the child had jaw muscle spasms (trismus). He was alert and requested water but was unable to open his mouth; respiratory distress caused by diaphragmatic and laryngeal spasm necessitated sedation, endotracheal intubation, and mechanical ventilation. Tetanus immune globulin (3000 units) and diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) were administered for presumed tetanus. He was admitted to the pediatric intensive care unit and cared for in a darkened room with ear plugs and minimal stimulation (stimulation increased the intensity of his spasms). Intravenous metronidazole was initiated, and the scalp laceration was irrigated and debrided.
His opisthotonus worsened, and he developed autonomic instability (hypertension, tachycardia, and body temperatures of 97.0 deg F-104.9 deg F [36.1 deg C-40.5 deg C]). He was treated with multiple continuous intravenous medication infusions to control his pain and blood pressure, and with neuromuscular blockade to manage his muscle spasms. A tracheostomy was placed on hospital day 5 for prolonged ventilator support. Starting on hospital day 35, the patient tolerated a 5-day wean from neuromuscular blockade. On day 44, his ventilator support was discontinued, and he tolerated sips of clear liquids. On day 47, he was transferred to the intermediate care unit. 3 days later, he walked 20 feet [6 m] with assistance. On day 54, his tracheostomy was removed, and 3 days later, he was transferred to a rehabilitation center for 17 days.
The boy required 57 days of inpatient acute care, including 47 days in the intensive care unit. The inpatient charges totaled USD 811 929 (excluding air transportation, inpatient rehabilitation, and ambulatory follow-up costs). One month after inpatient rehabilitation, he returned to all normal activities, including running and bicycling.
Despite extensive review of the risks and benefits of tetanus vaccination by physicians, the family declined the 2nd dose of DTaP and any other recommended immunizations.
This is the 1st pediatric tetanus case in more than 30 years in Oregon (unpublished data, Oregon Health Authority, 2018). The diagnosis of tetanus is made based on clinical findings because the bacterium _C.
tetani_ is difficult to grow from wounds. A wound culture from the child’s laceration did not grow _C. tetani_. However, a negative wound culture does not rule out disease. The health care costs to treat this child’s preventable disease were approximately 72 times the mean
(2012) cost of USD 11 143 for a US pediatric hospitalization (1). A recent report describing adult tetanus cases included hospital charges ranging from $USD 22 229 to USD 1 024 672 (2).
Widespread use of tetanus toxoid-containing vaccines (tetanus toxoid inactivated vaccine or a combination vaccine that contains tetanus
toxoid) and tetanus immune globulin for wound management has led to a 95% decline in the number of tetanus cases and a 99% decrease in the number of tetanus-related deaths since the 1940s (3). From 2009 to 2015, 197 tetanus cases and 16 tetanus-associated deaths were reported in the USA (4). Unvaccinated or inadequately vaccinated persons are at risk for tetanus, irrespective of age, and recovery from tetanus disease does not confer immunity (5).
Routine administration of a 5-dose DTaP series is recommended for all eligible children at 2, 4, and 6 months of age, then a dose at 15-18 months of age, and a 5th dose at 4-6 years of age. Booster doses of diphtheria and tetanus toxoids are recommended every 10 years throughout life (4). Uninsured or underinsured eligible children may receive vaccines at no cost through the Vaccine For Children program (<Caution-https://www.cdc.gov/vaccines/programs/vfc/index.html>). Resources to assist healthcare providers in discussing vaccination with their patients, including how to address questions, are available online (<Caution-https://www.cdc.gov/vaccines/partners/childhood/professionals.html>).
[Unlike most diseases, in tetanus, disease does not result in tetanus immunity. Clinicians should begin or continue active immunization with a tetanus toxoid-containing vaccine as soon as the person’s condition has stabilized. Unfortunately, this was refused by the child’s family.
Regarding DTaP or Tdap, upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case “d” and “p” denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations.
The “a” in DTaP and Tdap stands for “acellular,” meaning that the pertussis component contains only a part of the pertussis organism. – Mod.LL
Thank you very much for the discussion on quasispecies on TWiV 567! However, there was some grumbling about selection acting on groups, when selection should only act on individuals. My understanding was that individual selection was still occurring.
In classic population genetics, if one sequence is more fit than another, it will eventually become fixed in the population. However, this assumes that a sequence can be faithfully reproduced! It’s an assumption we often don’t even consider, since it is so often true. But, in RNA viruses, sequences cannot be faithfully reproduced.
Take an idealized example: Let’s say there is a specific sequence, Sequence A, that is The Most Fit. The naive assumption is that this sequence should become fixed as the virus replicates. But, none of this uber-sequence’s progeny will have that same sequence—RNA polymerases make too many errors. We can call the collection of sequences that resemble Sequence A, Quasispecies A.
Consider another sequence, Sequence B. It is not as fit as Sequence A. We can likewise call the collection of sequences that resembles Sequence B Quasispecies B. If the *average* fitness of Quasispecies B is higher than the *average* fitness of Quasispecies A, we should expect Quasispecies B to outcompete Quasispecies A. It does not matter that one of the sequences in the Quasispecies A collection is more fit than any other—it cannot spread without a high fidelity polymerase.
In other words, if Sequence A’s fitness is severely compromised by any mutations but Sequence B’s fitness is more tolerant of mutations, we should expect the collection of sequences that resemble sequence B to outcompete. Group selection is not occurring, but the emergent behavior appears like selection is operating on populations, not individuals.
This was my understanding of the concept, yet another, I suppose, to throw into the ring!
Dear TWIV consortium,
concerning the uncertainty y’all expressed when deciding whether the Berlin/London patient’s HIV could have been cured since everybody develops X4 tropic virus: That’s not necessarily correct. I would assume that both patients were tested for virus tropism and the result showed that the overwhelming majority of the virus quasipecies…sorry, strains were R5 tropic.
HIV strains often, but not always, tend to develop X4 tropism late in the course of the disease, i.e. once the patient’s CD4 cell count lowers. Exceptions to this rule include fresh infections with X4 tropic virus through IV drug use (thus eliminating the bottleneck which exists when infected through mucosal surfaces) or patients dying with only R5 tropic virus strains. No exact rules are known as to why or when X4 tropism develops, but it is not a given that it HAS to develop during the course of the disease. Some virus strains are even “dual-tropic”, meaning they’re able to utilize both coreceptors for entry.
While no one knows why it arises and exact mechanisms are also not defined, the electrostatic charge of the V3 loop (a part of the fusogenic gp120) as determined by its amino acid composition seems to play a considerable role (in silico tropism assays almost exclusively make use of the V3 loop sequence).
I hope to have been of some assistance, yours truly, Ben
PS: I’ve been backing y’all since you introduced your Patreon account, and I’ve yet to run into serious financial issues. It’s cheap people! Just do it!
PPS: The weather discussion is great. Leave as is please. It’s already dark here in Austria, but today was a gorgeous autumn day, sunny with just some white wisps in the sky, 19°C tops. All the leaves are turning now, just beautiful to behold!
PPPS: Be nice to Dickson. I know you’ve made an effort the last shows, just a gentle reminder!
Dear TViV team,
A question from TViV-569 on possible development and use of a CXCR4-based method of HIV infection cure that would be similar to those used for Berlin and London patients, is indeed interesting. However, I would like to emphasize that methods of cure (or achieving long-term remission) used for these two patients are exceptional and are not seriously considered as a strategy for essentially any HIV patients. Both Berlin and London patients had life-threatening forms of cancer, and that was the reason why an irradiation or chemotherapy followed by a transplant of donor hematopoietic stem cells was used. If these patients did not have cancer, they would have never been treated that way. Such a treatment is extremely risky, expensive, and it is very difficult to find an optimal donor. So even if a few more of such cases ever appear in the future, they will remain exceptional proof-of-concept cases. However, active research is ongoing on possible strategies to delete or mutate CCR5/CXCR4 for scenarios that would not involve total destruction of original myeloid stem cells by irradiation, and that would use autologous instead of allogeneic stem cells for transplantation. Here is a link to a recent review by Allen et al (2018): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304358/
For both patients, the reason for choosing a CCR5 delta32 version of a CCR5 gene to substitute for a wild type was that this is a naturally occurring mutation known to protect in its homozygous state about 1% of Caucasian population from being infected by R5-tropic HIV strains. (16% mutation frequency mentioned by Vincent includes heterozygotes, while only homozygotes are fully protected.) However, no such naturally occurring protective mutations are known for CXCR4. Moreover, deleting or mutating CXCR4 is lethal in mice. Even if such a mutation of CXCR4 is found that protects from X4-tropic HIV strains and that is safe for a patient, it should never be used on its own, either in a clinical context similar to Berlin/London cases or in a context unrelated to cancer. The reason is that in the majority of cases, R5-tropic or R5/X4-double-tropic strains, but not X4-tropic strains, are transmitted during the initial infection, thus establishing themselves as transmitted/founder strains that give rise to the infection at the organism level. For example, Wilkin et al (2007) found that in ART-experienced individuals, 50% viruses were R5, 46% R5/X4, and only 4% X4: https://academic.oup.com/cid/article/44/4/591/341290 The prevalence of X4 strains seems even less in ART-naive individuals. Therefore, the use of any possible CXCR4 mutation alone would be completely irrational and even unethical, and only a combination of mutations of both CCR5 and CXCR4 should be used, provided that such a combination would be safe and efficient.
So, while this question is indeed very good for an exam, I would say students would be able to give the best answer if they are already familiar with the concept of a transmitted/founder virus, and with the prevalence numbers for R5, X4 and R5/X4 strains.
Finally, about the question of what was the HIV tropism in Berlin and London patients. For Berlin patient, an original sequence analysis by Yukl et al (2013) predicted that this patient had pre-existing X4 strains: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649997/ However, Symons et al (2014) performed phenotypic tests on co-receptor usage and concluded that those strains were CCR5-dependent: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990826/ This is a good illustration on the importance of doing phenotypic assays and limitations to using viral DNA/protein sequences for co-receptor usage. (I don’t know why the authors of the review that I linked to above, Allen et al, don’t cite Symons et al, writing instead that Berlin patient had X4 strains; maybe they missed Symons study?) For London patient, Gupta et al (2019) established the absence of pre-existing X4 strains: https://www.repository.cam.ac.uk/bitstream/handle/1810/290071/gupta%20et%20al.pdf?sequence=2&isAllowed=y Even though the exact mechanism of virus clearance remains unknown, for both cases Gupta et al suggest mild graft-versus-host disease as an unconfirmed hypothesis.
I was hoping to keep it short, but I did my best 🙂
Keep up your great work!