Immune stimulation by vaccination e.g. Staphylococcus Toxoid Vaccine, BCG

[forestglip]

Long-Term Treatment with a Staphylococcus Toxoid Vaccine in Patients with Fibromyalgia and Chronic Fatigue Syndrome

Carl-Gerhard Gottfries, Ove Häger, Björn Regland, Olof Zachrisson

Abstract
One hundred and sixty patients with fibromyalgia and chronic fatigue syndrome, who were on a continuous treatment with a Staphylococcus vaccine, were followed during one year with repeated consultation visits. The patients had participated in controlled studies and been on continuous treatment with the vaccine for 22±10 months before inclusion into this follow-up study. They were treated with 1 mL of the vaccine subcutaneously every third to fourth week. Adverse events were few.

The adherence to the treatment was very good. Over a period of one year, 8% withdrew, and in only 5%, the withdrawal was due to insufficient clinical effect. Only in two cases where the patients were allergic to the preservative of the vaccine, the side effects caused the withdrawal of the treatment.

Ratings with scales (CPRS-15 and FibroFatigue) showed improvement from start of treatment and also further improvement during the follow-up year. In view of the natural history for these disorders the result is of interest.

Link (Journal of Chronic Fatigue Syndrome) [Paywall]

 

[forestglip]

In 2009, there was a full text of what appears to be the same study, but with a differently worded abstract, published in Bulletin of the IACFS/ME:

Snippets from sections:

Background

In order to modulate the immune system, we have performed clinical trials using a staphylococcus toxoid vaccine (Staphypan) (17). The results from two double-blind placebo-controlled trials, where the patients fulfilled the criteria for FM and CFS have been published (18, 19). The patients received weekly subcutaneous injections in increasing dosages of the vaccine during the initial 8-10 week period, and thereafter once a month. A positive clinical effect was recorded in 65 % of patients on active treatment according to global ratings. The items fatigability, reduced sleep, failing memory, concentration difficulties, hostile feelings and sadness improved significantly more in the active group compared to the placebo group. During a two-month controlled and blind withdrawal period, however, most responders relapsed and they were therefore offered maintenance treatment.

Methods

Enrollment beginning in Oct 2003 included 160 patients, 9 men and 151 women of whom 80 had the diagnosis of FM, 18 of CFS and 62 fulfilled the criteria for both diagnoses. All patients were cared for at our outpatient unit. The mean age at study entry was 53±11 (SD) years. The patients were recruited from previous controlled studies, as follows:

a) a pilot study (non published), which started in 1993 with the aim of testing the
administration and dosing of the vaccine;
b) the first double blind placebo controlled study which was completed in 1998 (n=28)
(18);
c) the second double blind study completed in 2001 (n=100) (19).

CPRS comprises 65 items covering a broad range of psychiatric symptoms. The CPRS- 15 sub scale includes fifteen items assumed to be of interest for rating symptoms in patients with FM and CFS (see table 2). Each item is rated according to a 7-step scale in which the scale steps 0, 2, 4 and 6 are defined. The maximum score is 90 and the scale is assumed to be sensitive to change over time. The patients were rated with CPRS-15 before any vaccine treatment and every third month during the one year duration of this long-term study.

Results

Patients were rated with the CPRS-15 scale before start of vaccine treatment and achieved a mean score of 33±7.5. At the inclusion in this one-year follow up study the patients had been on the immunotherapy for a mean of 22 ±10 months. Reassessment with CPRS-15 then showed improvement compared to baseline; the mean score was 20.7 ± 8.5 points (p<0.02). A further significant reduction of the mean score to 14.6±7.4 (p<0.05) was seen during the 12 months continued vaccine treatment indicating improvement more than two years after start of treatment (Table 1).

According to the definition of the items, a rating level below one is considered normality. Five items (Concentration difficulties, Failing memory, Irritability, Sadness and Autonomic disturbances) had mean levels below one at the time of the last rating, indicating that these symptoms on a group level were within the range of normality. Three items, aches and pain, fatigue and sleep disturbances, were significantly reduced, however, not to mean levels below one. The item muscular tension did not improve significantly (Table 2).

Discussion

In a previously published study (24) 14 patients receiving active treatment with the staphylococcus vaccine and 14 receiving placebo, anti-body status against extracellular toxins/enzymes, cell-wall components, and enterotoxins was evaluated in serum at baseline and after six months treatment. Significant changes were recorded in the group with active treatment while no change was seen in the controls. Treatment led to increased capacity of serum to neutralize alpha-toxin (p< 0.001) and a significant increase in serum IgG to alpha-toxin (p< 0.01) and lipase (p< 0.01). Furthermore, the increase in the serum parameters paralleled the improvement in clinical out-come. Thus, the greater the serological response, the greater was the clinical effect. This relationship may indicate a working mechanism of the vaccine. [Previous study]

Limitations

The long-term study presented here was not blinded, however, it was preceded by two controlled studies performed according to the double blind technique. Further controlled studies with a staphylococcus vaccine are important to prove the effect.

 

[forestglip]

How has this not been tested again?

I found this group's results cited as recently as 2018 and 2022, with no mention of newer studies on the vaccine.

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model, 2018, Blomberg et al

Immunostimulation, e.g., with Staphylococcal vaccine, theoretically could induce tolerance to autoepitopes involved in ME/CFS pathogenesis (265–267). It was reported to be effective in ME/CFS in a double-blind study (267). Symptom relief paralleled anti-staphylococcal antibody presence (266), arguing for impaired development of tolerance to autoepitopes of microbial origin in ME/CFS. Further studies are needed.

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?, 2022, Kavyani et al

Alternative to FMT is immune stimulation therapy with the use of bacteria toxin such as the Staphylococcal toxoid vaccine. This vaccine generates a serological response to several staphylococcal antigens, particularly to certain extracellular toxins and enzymes. Although immune responses in ME/CFS patients have not been agreed on, responses to this vaccine have been reported to be fruitful in the clinical outcome of treatment.

There were two RCTs that have examined its impact on a patient with ME/CFS. The first RCT reported significant benefits to the patients whereby improvement in pain and psychometric assessment was reported after vaccination when compared to controls receiving sterile water injections [61].

A second RCT study continues with the follow-up of the patients in the first RCT for 6 months after the administration of the second shot. The outcome of the second study shows a highly favourable outcome where 50% of patients were more functional by rehabilitating successfully and resuming half-time or full-time work confirmed the benefits for the patients [40].

Maybe because of adverse events?

Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review, 2006, Chambers et al

Two new studies of immunological therapies (a controlled trial of inosine pranobex35 and a relatively low quality RCT of staphylococcus toxoid36) were added to the updated review. Both of these treatments showed benefits for some outcomes but were also associated with relatively high levels of adverse events. Overall there is still insufficient evidence about the effectiveness of therapies of this type.

36 is the following, which is a previous staph study by the same authors. Mentioned in the study for this thread.

Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a randomised controlled trial, 2002, Zachrisson et al

A total of 100 eligible female patients were recruited and randomised to receive the study drug (SB, n = 50) or placebo (n = 50).

Treatment with SB over 6 months was well tolerated. A total of 10 randomised patients discontinued treatment prematurely (placebo n = 5, SB n = 5). Two patients dropped out before any assessments of treatment efficacy were made, one because her husband died and the other because of the discovery of hypertension that needed medical treatment. All the patients had a local reaction at the site of the injection but to preserve blindness, the severity of these reactions was not rated. Headaches were reported more often in the SB group (P < 0.05; Table 5).

Eight patients discontinued the treatment programme (placebo n=4, SB n=4). The reasons for discontinuation in the SB group were (1) headache (week 4), (2) allergic reaction due to the salicylate compound of preservatives (documented by lymphocyte proliferation test; week 8), (3) angina pectoris (week 16), and (4) depression (week 16). In the placebo group, patients dropped out because of (1) lost interest (week 4), (2) no given reason (week 8), (3) starting with antidepressant treatment (week 16), and (4) increased pain (week 16).

Overall side effects of the drugs were assessed at endpoint using the clinical global impression of side effects (Table 5). According to these ratings, 13 SB patients (26%) and 7 (14%) placebo patients had experienced side effects of the treatment. The difference did not reach statistical significance (P = 0.14)

This does not seem adverse enough to never try it or anything similar again for 20 years.

 

[mango]

How has this not been tested again?

Because the manufacturer of this particular vaccine stopped making it, supposedly (based on what I've been told by Gottfries' patients years ago).

 

[forestglip]

Because the manufacturer of this particular vaccine stopped making it, supposedly (based on what I've been told by Gottfries' patients years ago).

Yeah, they say that in the above paper:

Berna Biotech informed us at 2005 that Staphypan would be withdrawn from the market. Staphypan was an old product where the manufacturing process had to be developed to cope with modern GMP rules in EU and US. The present owner of Berna Biotech, the company Crucell in the Nederlands will not take any economic or medical responsibility for developing a modern Staphypan.

We have tried to find a vaccine that could replace Staphypan but there is no such product at least in the western world. At present we make efforts to develop a Staphypan-like product for use in further clinical investigations. We assume that a vaccine treatment of the kind presented here eventually due to a super-antigen effect, can be of use for patients with CFS, FM and possibly other immune deficiency syndromes.

But still, I don't see why similar vaccines aren't tested. I'd be very surprised if that's the only possible vaccine that could provide a benefit. Some people with ME/CFS even report a temporary benefit from the COVID vaccine.

 

[mango]

I agree with you, @forestglip. I'd love to see this explored and tested properly.

A side note, there's a thread from 2015 on PR about the closing down of the Gottfries' clinic. I don't know the whole story myself, but it's very clear that the BPS lobby was doing everything they could to put Gottfries down, including going after their research and treatments efforts through political means behind the scenes.

 

[mango]

There's a 5 part series of videos on YouTube, an interview with prof Gottfries from 2014. He talks about his reseach (but I can't remember any details at the moment, it's been so many years since I last watched it).

Interview with Professor Carl-Gerhard Gottfries, Part 1: Background and Vaccine


Interview with Professor Carl-Gerhard Gottfries, Part 2: Experience and The Clinic


Interview with Professor Carl-Gerhard Gottfries, Part 3: The Clinic and Urgent Needs


Interview with Professor Carl-Gerhard Gottfries, Part 4: Continued Research


Interview with Professor Carl-Gerhard Gottfries, Part 5: Wishes For The Future

 

[forestglip]

There's a 5 part series of videos on YouTube, an interview with prof Gottfries from 2014. He talks about his reseach (but I can't remember any details at the moment, it's been so many years since I last watched it).

Interview with Professor Carl-Gerhard Gottfries, Part 1: Background and Vaccine


Interview with Professor Carl-Gerhard Gottfries, Part 2: Experience and The Clinic


Interview with Professor Carl-Gerhard Gottfries, Part 3: The Clinic and Urgent Needs


Interview with Professor Carl-Gerhard Gottfries, Part 4: Continued Research


Interview with Professor Carl-Gerhard Gottfries, Part 5: Wishes For The Future

Thanks! I'll definitely try to watch those.

 

[bobbler]

There's a 5 part series of videos on YouTube, an interview with prof Gottfries from 2014. He talks about his reseach (but I can't remember any details at the moment, it's been so many years since I last watched it).

Interview with Professor Carl-Gerhard Gottfries, Part 1: Background and Vaccine


Interview with Professor Carl-Gerhard Gottfries, Part 2: Experience and The Clinic


Interview with Professor Carl-Gerhard Gottfries, Part 3: The Clinic and Urgent Needs


Interview with Professor Carl-Gerhard Gottfries, Part 4: Continued Research


Interview with Professor Carl-Gerhard Gottfries, Part 5: Wishes For The Future

interesting on starting part 4 already. He says that originally the 3 of them came from psychiatry, but that it became clear it was something immunological ie the illness isn't psychiatric

And just because of the 'which speciality' discussion elsewhere I'll note he then confirms there is now 3 psychiatrists, one gerontologist, one internist and research nurses

 

[forestglip]

These interviews were very interesting. I've transcribed the parts I found most interesting. Note that I wasn't 100% accurate with the transcriptions. Reworded some parts to make them clearer or more succinct, and skipped some parts, and may not have put [...] at every part I skipped.

Interview from February 2014

Video 1

Yeah, it's rather peculiar because I'm a professor of psychiatry, and chronic fatigue syndrome is not a psychiatric disorder. And I'm treating the patients with vaccines, and that's not a useful treatment in psychiatry either.

The reason [...] it was 1957 and 1958. At that time, the Asian Flu ravaged in Sweden. I had many patients in my psychiatric unit who came there because they were so tremendously tired. They couldn't work, and internal medicine couldn't find any explanation to their fatigueness, so they then refer them to the psychiatric unit, assuming this was some kind of psychiatric disorder. I investigated them carefully [...] and found that they were quite normal people, and they complained of tiredness. And in almost all of them, they said "I had the Asian Flu a couple of months ago" and since then I have felt so tired that I can't work any longer.

I got the Asian flu myself, and was rather ill for one week. and experienced the same thing as my patients. [...] I was quite convinced of myself that my infection hadn't disappeared. [,,,] A little naively, I thought that if I take vaccines myself, I can activate my immune system, and in that way, perhaps I can get rid of this infection feeling. And to make a long story short - it was a long story because I kept on for at least three years - [...] if I took a special staphylococcus vaccine where some toxoid was added which gives this vaccine a super antigen effect...if I took that, I improved. And these fatigue symptoms disappeared.

And I of course started to treat patients. And they improved also. And my head physician didn't really like that so I had to stop there. But I continued myself to take this vaccine. And I had to take it every month. So it was not really a vaccine treatment. It was an immune stimulant treatment. And I still take this vaccine, every month, now since 50 years. Because if I stop, I get a relapse of my fatigue.

Together with professor of immunology at the Karolinska institute showed that this vaccine gave rise to antibody titers, especially antibodies against some toxins could be correlated to the clinical effect.

When I approached my retirement, I said now I must make research of this kind of treatment. So I started this unit I have now, here.

That company withdrew that vaccine from the market despite our heavy protests. [...] The manufacturing process had to be improved to fit with the rules of the EU and US, and they didn't want to do that.

I had an agreement with the medical authorities. I can see patients here and in parallel to this, I can make research. And then we made two double blind controlled investigations. Where we included in the first one 28 patients, and in the second one 100 patients. And treated them either with active vaccine, or colored distilled water. Because if you give patients distilled water in an injection, it gives rise to pain similar to what the vaccine gives. And then when doing these two controlled studies, we could really prove the concept. We could show that 65% of the patients improved. There were quite a few that improved so much that the symptomatology was reduced by more than 50%.

Video 2

We had about 250 patients who were taking it. 205 had to stop when it was withdrawn. [...]

The diagnostic criteria we use is the Fukuda [...]. Later on more strict criteria has been presented named the Canada criteria, and now we use that in research. We also use the International Consensus Criteria sometimes.

We are very interested in studying treatment of these patients with vitamin B12 and folic acid [...] and we have noticed that chronic fatigue patients who very often complain of brain fog, they say if they get high doses of vitamin B12 injections every week, this brain fog disappears. At present we are trying to make research to see if there is any disturbance of the transport of B12 and folic acid. It could be so that the transport from the blood into the brain is disturbed. We always combine B12 and folic acid, because these two vitamins take part in a very important process which is usually named the 1 carbon metabolism.

[And you are now in the process of starting a study together with Open Medicine in California?]

Yes, we are now planning a study where we shall treat them with vitamin B12 plus folic acid in a double blind methodology to see if we can prove that the brain fog disappears with these vitamins.

Video 3

We are still very unique in Sweden, we are the only such unit in Sweden. But now a private unit has opened in another county. And in Stockholm there is project going on where they will take care of these patients.

There should be more such units like this. The people who work with these patients have to know the symptomatology of these patients have to know the symptomatology of these disorders and the understanding of how much they can function. How their energy is lost, and sometimes they have post-exertional malaise where they get very tired for a couple of days after some heavy work.

You should give time for patients. We give every first visit one and a half hours, really to get through all the symptoms they have. When they get here, they've been ill on average 11 years before getting a diagnosis.

Video 4

Professor of virology at the university of Rupsula (sp?) What he has found is that there are antibodies against a protein which is called the heat shock protein, which you'll find in the mitochondria. He found that in about 30 to 40 percent of ME/CFS patients. Due possibly to infections, there is possibly an autoimmune process starting in these patients and disturbing the cell metabolism and energy production.

[Regarding Vitamin B12 for brain fog]

Effect comes rather soon.

B12 and folic acid collaborate in the methylation of homocysteine. [...] Because homocysteine is toxic in itself. What we then did is we took a spinal tap from patients with CFS. Of 12 patients, 10 had to low levels of B12. And there was one who had a very pathological low level of vitamin B12. Still more interesting, when we measured homocysteine, we could show that chronic fatigue patients had increased levels of this homocysteine.

To the left there are 11 patients with homocysteine levels in the cerebrospinal fluid, while the other two groups are two different control groups.

When we investigated the gene expression for the MTFHR then those who had a mutation on this did not respond. This was made blind. The way we think about this is that possibly the transport of at least B12 is disturbed in these patients.

Video 5

[If you could have a wish in this area, what would that be?]

Could I have two wishes? The first wish is of course that I would still like to have back this staphylococcus vaccine because then we really proved the concept. It works., according to scientific investigations. I have put this wish to all big pharma in the world. [...] They didn't do it. One reason "is this really a disorder? We really don't rely upon that. So many doctors that say it's nothing."

The other wish is that you must start units like this, so that we can bring up the problem to the surface, and show it for both sponsors and researchers. Because it's an interesting field to make research on.

I wonder what he's doing now. He seems like quite a nice fellow from this interview.

 

[mango]

I wonder what he's doing now. He seems like quite a nice fellow from this interview.

I don't know what he's doing now, but I believe he's currently about 96 years old?

And yes, he's been very much appreciated by his patients and the ME community over the years.

 

[forestglip]

I don't know what he's doing now, but I believe he's currently about 96 years old?

Wow, well then I hope he's still alive and just relaxing. (Unless he wants to work of course)

 

[Turtle]

There's a 5 part series of videos on YouTube, an interview with prof Gottfries from 2014. He talks about his reseach (but I can't remember any details at the moment, it's been so many years since I last watched it).

Interview with Professor Carl-Gerhard Gottfries, Part 1: Background and Vaccine

Really great find @forestglip and great follow up @mango, many thanks.

I watched the first video.
Prof. Gottfries started in 1957, the year I was born.
A 50% of reduction of symptons because of this vaccine, injected once a month, could have been available when I got ME/CFS in 1991.

The BPS-lot stole half my life.

 

[forestglip]

Here are the two RCTs they performed:

Effects of staphylococcus toxoid vaccine on pain and fatigue in patients with fibromyalgia/chronic fatigue syndrome, 1998, Andersson et al

Positive results of pilot studies of the effect of staphylococcus toxoid vaccine in patients with fibromyalgia and chronic fatigue syndrome were the incitement to the present, placebo-controlled study. It included 28 patients who fulfilled the criteria for both fibromyalgia and chronic fatigue syndrome. The effect of vaccination with a staphylococcus toxoid was compared with the effect of injections of sterile water. Psychometric assessment was made using 15 items from the comprehensive psychopathological rating scale (CPRS), Zung's self-rating depression scale and clinical global impressions (CGI). The visual analogue scale (VAS) was used to measure pain levels, and a hand-held electronic pressure algometer was used to measure pressure pain thresholds.

Significant improvement was seen in seven of the 15 CPRS items in the vaccine group when pretreatment values were compared to post-treatment values. In CPRS ‘fatiguability';, there were significant intergroup differences, and in CPRS ‘pain'; intergroup differences bordered on significance. There was no significant improvement in CPRS items in the placebo group. Clinical global impressions showed significant improvement in the vaccine-treated group, and VAS did so in both groups.

In a follow-up study of 23 patients, the vaccine treatment was continued for 2–6 years. Fifty percent were rehabilitated successfully and resumed half-time or full-time work.

The results of this study support the authors' hypothesis that treatment with staphylococcus toxoid may be a fruitful strategy in patients with fibromyalgia and chronic fatigue syndrome.

Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a randomised controlled trial, 2002, Zachrisson et al

We have previously conducted a small treatment study on staphylococcus toxoid in fibromyalgia (FM) and chronic fatigue syndrome (CFS). The aim of the present study was to further assess the efficacy of the staphylococcus toxoid preparation Staphypan Berna (SB) during 6 months in FM/CFS patients.

One hundred consecutively referred patients fulfilling the ACR criteria for FM and the 1994 CDC criteria for CFS were randomised to receive active drug or placebo. Treatment included weekly injections containing 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml, 0.9 ml, and 1.0 ml SB or coloured sterile water, followed by booster doses given 4-weekly until endpoint.

Main outcome measures were the proportion of responders according to global ratings and the proportion of patients with a symptom reduction of > or =50% on a 15-item subscale derived from the comprehensive psychopathological rating scale (CPRS).

The treatment was well tolerated. Intention-to-treat analysis showed 32/49 (65%) responders in the SB group compared to 9/49 (18%) in the placebo group (P<0.001).

Sixteen patients (33%) in the SB group reduced their CPRS scores by at least 50% compared to five patients (10%) in the placebo group (P< 0.01). Mean change score on the CPRS (95% confidence interval) was 10.0 (6.7-13.3) in the SB group and 3.9 (1.1-6.6) in the placebo group (P<0.01). An increase in CPRS symptoms at withdrawal was noted in the SB group.

In conclusion, treatment with staphylococcus toxoid injections over 6 months led to significant improvement in patients with FM and CFS. Maintenance treatment is required to prevent relapse.

-----------

Second one does appear to be double blind. (Maybe first one too, I haven't looked yet.)

Assignment to the treatment group was carried out via a computer-generated randomisation code with a block size of 10. The study drug, provided by SSVI, Berne, was kept in 1-ml ampoules and packed in boxes marked with patient numbers. So was the placebo drug, which was composed of sterile water similar to SB in colour. Included patients were numbered consecutively and treated with SB or placebo from the boxes with their randomisation numbers.

Both the active substance and the placebo caused a slight local pain and reaction after injection. The injections were given subcutaneously in the gluteal region by a nurse, but not the one who assessed the effect of the treatment by ratings. The reason for this was that a careful investigation of the local reactions could possibly differentiate placebo from vaccine, the latter causing a longer-lasting local reaction. The drugs were administered at increasing doses of 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml, 0.9 ml, and 1.0 ml weekly, followed by booster doses of 1.0 ml every 4 weeks. The last injection was given at week 24 and endpoint ratings were performed at week 26. Blind ratings were repeated at week 32 for evaluation of withdrawal effects. After the controlled study was completed, all the patients were offered active treatment.

One thing I was wondering was if these patients had previously been receiving this treatment at the clinic, in which case they might be able to detect presence or absence of certain known side effects. But I think they would have included that in the paper and I don't see that.

The study was conducted in a special unit at
Sahlgrenska University Hospital in M€oolndal, Sweden, to which patients were referred from primary care centres in the area. Female patients (18–65 years) were eligible for the study if they (1) met both the ACR diagnostic criteria for FM and the CDC criteria for CFS and (2) presented a functional impairment related to these syndromes as documented by > 6 months of full- or part-time sick-leave. In accordance with the criteria outlined for CFS, most of the patients had a status, indicating ongoing mild immune activation such as low-grade fever or a sore throat. They were allowed to continue with prescribed medication during the study, as long as they were in a steady state.

Possibly didn't have PEM if they used CDC criteria, but they did have "mild immune activation".

 

[hinterland]

That company withdrew that vaccine from the market despite our heavy protests. [...] The manufacturing process had to be improved to fit with the rules of the EU and US, and they didn't want to do that.

Finally, an upside to Brexit? We could start up the old company again with the original manufacturing process.

I think part of the issue was that the vaccine contained mercury-based preservatives and so I’m quite glad these were deemed in need of improvement, but apparently that would also necessitate going through the whole, expensive, regulatory approval process again. Potentially costing 100s of millions of dollars. It’s a real shame; I’d like to see a new improved staph toxoid vaccine approved and tested for ME/CFS. Anyone know any organisations or wealthy individuals willing to fund this project?

 

[forestglip]

Looking at this paper, the second RCT by Gottfries:
Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a randomised controlled trial, 2002, Zachrisson et al

In 16 cases, onset was related to an acute infection and in 15 cases, onset was related to pregnancy and/or delivery.

I haven't heard much about pregnancy being a trigger.

The original CPRS comprises 65 items covering a broad range of psychiatric symptoms. There are seven scale steps for each item, with 0 indicating normality and 6 indicating maximum severity of a symptom. In the present study, 15 items measuring symptoms of interest in FM and CFS were selected from the CPRS. The subscale, called CPRS-15, is presented in Table 1.

Here are all the symptoms tested, with a star next to those that had significant improvement at 26 weeks. The number is the baseline score for the active group.

*4.8 Fatiguability
4.8 Aches and pains
*4.0 Reduced sleep
3.4 Muscular tension
*2.9 Failing memory
*2.8 Concentration difficulties
2.5 Autonomic disturbances
*2.2 Hostile feelings
*1.7 Sadness
1.3 Inner tension
1.1 Pessimistic thoughts
1.0 Worrying over trifles
0.8 Suicidal thoughts
0.5 Hypochondriasis
0.4 Phobias

That it seems to continue to improve more and more with time makes me think that assuming there is viral persistence, it is doing more than keeping the infection at bay. It seems that it is slowly chipping away at it with time, and that maybe a larger dose or more effective vaccine could do so more quickly. Although it did still return to near placebo level after withdrawal.

"Good responders" means "One-third (33%, n = 16) of the 49 patients receiving active treatment were classified as good responders (>50% reduction in scores at end-point)."

Here is one of the secondary outcomes, a different rating scale "Clinical global impression of change (CGI-C)":

The severity of illness was rated from 1 to 7, with 1 indicating normal (‘not ill at all’ and 7 indicating ‘among the most extremely ill patients’. Improvement was recorded at endpoint and after withdrawal using the clinical global impression of change (CGI-C) (Guy, 1976). Improvement was rated from 1 to 7, with 1, 4, and 7 indicating ‘very great improvement’, ‘no change’, and ‘very great impairment,’ respectively. Three trained research nurses performed the global ratings.

The mean change score (95% confidence interval) was 0.5 (0.3–0.8) in the SB group and 0.1 (0.0–0.2) in the placebo group (Mann–Whitney U test; P < 0.01). No significant changes were seen at withdrawal.

Two other secondary outcomes were related to pain, "Visual Analogue Scale (VAS) of Pain", and "Fibromyalgia Impact Questionnaire (FIQ)".

[VAS] Student’s t test of change scores from week 0 to week 26 shows significantly greater improvement in the SB group compared to the placebo group (P < 0:05). Change scores were 1.4 (0.6–2.2) in the SB group and 0.1 (-0.5–0.7) in the placebo group. At week 12 change scores were 1.2 (0.4–1.9) for the SB group compared to 0.2 (-0.4–0.9) in the placebo group. The difference borders on significance (P = 0.057). At withdrawal the patients in the SB group rated their pain as getting worse as reflected by an average increase in VAS scores of 1.1 points (0.5–1.7) (P < 0.001), while there was no significant change in the placebo group (average change score of 0.1 (-0.4–0.6).

As is evident from Table 3, the total FIQ score decreased from week 0 to week 26 by 0.9 points (0.4–1.4) in the SB group and by 0.3 (-0.2–0.8) in the placebo group (P = 0.067). The only single item that was significantly changed at week 26 was ‘feeling good’ (P < 0.05) and the change was in favour of SB treatment. Change in tiredness bordered on significance (P = 0.052), also favouring SB treatment. During the withdrawal phase, ‘feeling good’ was the only item in the SB group that worsened on a significant level (P < 0.05).

So it doesn't seem pain was much improved.

In regard to pain evaluation, the effect was significant according to VAS but did not reach statistical significance in the CPRS ratings. One conclusion of this is that the effect of treatment is most prominent in CFS. If the effect of treatment is also of clinical importance in pure fibromyalgia states is at present impossible to say and further studies are needed on this topic. According to our clinical impression, it seems that SB treatment is of clinical value also in fibromyalgia alone.

Concerning blinding:

A substantial placebo effect was found, which may be interpreted as an indication of successful blinding.

Side effects:

Although not rated, a local reaction at the site of injection was frequent and some patients reported malaise and sickness symptoms, such as fever, during the first few days after an injection. Headaches were more common among patients with active treatment and most common during the last part of titration. Two patients who were allergic to the salicylate compound of the preservative (validated by lymphocyte proliferation tests) had a rather severe headache and also a more profound local reaction. One of these patients dropped out after 8 weeks of treatment while the other one managed to complete the programme.

Susceptibility to infections:

At baseline, most of the study patients were clinically found to be prone to infections. According to clinical judgement, several patients on active treatment improved with regard to their sensitivity various infections. Although not statistically significant, they also less often did report infection as adverse events during the trial (5 cases) than did patients in the placebo group (11 cases; Table 5)

Interesting, considering the opposite observations often made by researchers/clinicians (I think I've heard of researchers saying this) and patients that people with ME/CFS report fewer infections.


Something about nickel allergy and smoking:

During the trial we noted a tendency of reduced clinical response among patients with a clinical history of nickel allergy and especially if they were also cigarette smokers. This association was later confirmed in a separate study (Regland et al., 2001). However, in the present study, nickel allergy was equally common in the treatment and placebo groups and so was concomitant smoking

Will have to check what that Regland paper is.


Mechanism speculations

Administration of staphylococcal antigens is related to activation of both humoral and cell-mediated mechanisms. However, as the staphylococcal pathogen shares some of the properties of intracellular disease agents, the defence mechanism primarily involves the cell-mediated immune system (Mudd, 1971; Murphy, 1991). Reports from the literature suggest that administration of staphylococcal antigens may work as an unspecific inducer of cell-mediated immunity. For instance, experiments with the staphylococcal vaccine Staphage Lysate (SPL) has been shown to be a potent immune stimulant, especially on the T-lymphocytes (Dean et al., 1975).

The preparation has also been reported to induce cytokines promoting T helper subclass 1 (Th1) cellular immunity. This is of some interest, since the defence against infections is primarily said to be dependent on Th1- driven mechanisms. Furthermore, in laboratory animals, treatment with SPL were found to provide non-specific protection against other infectious agents (Shayegani et al., 1980). In parallel to these findings, one may hypothesise that repeated administration of Staphypan Berna leads to an enhancement of cell-mediated immunity related to changes in the Th1/Th2 cytokine balance.

There are also sporadic reports from the literature suggesting more specific mechanisms of action. Australian investigators have hypothesised membrane-damaging toxins from coagulase-negative staphylococci (McGregor et al., 1996; Butt et al., 1998) to play a role in the aetiology of chronic muscle pain. Case reports have been published by Tarello (2001) on chronic fatigue syndrome associated to Staphylococcus bacteremia.

Cytokines secreted after local inflammation may induce hypersensitivity to pain by binding to endothelial cells of the blood-brain barrier, leading to the synthesis of prostaglandin E2 (Ek et al., 2001). This highly active, inflammatory, fever-inducing, and pain-causing signal can enter the cerebrospinal fluid and activate immune cells (microglia) of the brain. Once activated, microglia produce interleukin-1b, leading to further synthesis of prostaglandin E2 but now within the brain (Samad et al., 2001). One may speculate that SB treatment leads to a different cytokine response affecting this ‘pain pathway’

Formulation:

The preparation used, Staphypan Berna (SB; manufactured by Swiss Serum and Vaccine Institute, Berne; SSVI, Berne), is composed of undefined extracts of two strains of staphylococci, S. aureus and S. epidermidis, and a preservative compound, thiomersal.

The preparation used contains the preservative thiomersal (which dissociates into a mercury salt and salicylate after being injected) and is an old vaccine synthesised by methods that do not match up to modern legal standards

Hmm, injecting mercury doesn't sound too great.

One thing we can see is that Dr. Gottfries took this for around 50 years, and in his interview at 85 or 86 years old still seems quite healthy, so no obvious evidence of severe negative health effects in that specific case.

 

[forestglip]

The RCT mentioned this paper, where Gottfries is also an author:

--------

Nickel Allergy is Found in a Majority of Women with Chronic Fatigue Syndrome and Muscle Pain—and may be Triggered by Cigarette Smoke and Dietary Nickel Intake, 2001, Regland et al
Bjorn Regland, Olof Zachrisson, Vera Stejskal, Carl Gerhard Gottfries

Abstract
Two hundred and four women with chronic fatigue and muscle pain, with no signs of autoimmune disorder, received immune stimulation injections with a Staphylococcus vaccine at monthly intervals over 6 months. Good response was defined as a decrease by at least 50% of the total score on an observer's rating scale.

Nickel allergy was evaluated as probable if the patient had a positive history of skin hyper-sensitivity from cutaneous exposure to metal objects. The patient's smoking habits were recorded. Fifty-two percent of the patients had a positive history of nickel contact dermatitis.

There were significantly more good responders among the non-allergic non-smokers (39%) than among the allergic smokers (6%). We also present case reports on nickel-allergic patients who apparently improved after cessation of cigarette smoking and reducing their dietary nickel intake.

Our observations indicate that exposure to nickel, by dietary intake or inhalation of cigarette smoke, may trigger systemic nickel allergy and contribute to syndromes of chronic fatigue and muscle pain.

Link | PDF (Journal of Chronic Fatigue Syndrome) [Paywall, but the full text PDF linked is available from a website called MELISA.org]

 

[MeSci]

I don't think much of these:

"Here are all the symptoms tested, with a star next to those that had significant improvement at 26 weeks. The number is the baseline score for the active group.

*4.8 Fatiguability
4.8 Aches and pains
*4.0 Reduced sleep
3.4 Muscular tension
*2.9 Failing memory
*2.8 Concentration difficulties
2.5 Autonomic disturbances
*2.2 Hostile feelings
*1.7 Sadness
1.3 Inner tension
1.1 Pessimistic thoughts
1.0 Worrying over trifles
0.8 Suicidal thoughts
0.5 Hypochondriasis
0.4 Phobias"

Many of these are psychiatric symptoms which are not part of ME. And where is possibly the most important symptom - post-exertional malaise (PEM)?

 

[forestglip]

I don't think much of these:

"Here are all the symptoms tested, with a star next to those that had significant improvement at 26 weeks. The number is the baseline score for the active group.

*4.8 Fatiguability
4.8 Aches and pains
*4.0 Reduced sleep
3.4 Muscular tension
*2.9 Failing memory
*2.8 Concentration difficulties
2.5 Autonomic disturbances
*2.2 Hostile feelings
*1.7 Sadness
1.3 Inner tension
1.1 Pessimistic thoughts
1.0 Worrying over trifles
0.8 Suicidal thoughts
0.5 Hypochondriasis
0.4 Phobias"

Many of these are psychiatric symptoms which are not part of ME. And where is possibly the most important symptom - post-exertional malaise (PEM)?

Yeah, he was going by Fukuda/CDC criteria in his practice originally. CCC and ICC weren't created until after this paper, and the paper doesn't mention PEM.

 

[EndME]

In regards to BCG, there were an abundance of different trials on different BCG formulations with tens of thousands of participants to see whether there is an impact on acute Covid (I don't think any had a Long-Covid follow-up). At the beginning of the pandemic there was the speculation that certain regions in the world (for instance Africa and Latin America) were doing better with acute Covid and some speculated that this could be due to BCG vaccination status, given the tremenounds amount of funding for acute Covid it was really easy for them to launch trials. It seems the results were a rather mixed bag, with largely negative results.

Similarly there has been a large study on BCG vaccination and MS risk. I'm sure there's hundreds of other studies for different conditions as well.

I know that even today, there are ME/CFS patients groups still experimenting with different formulations of BCG vaccines.