14 december Episode 202 Omicron and fertility

Episode 202

OMICRON

Ep 202-1:  Lu Lu medRxiv 13 Dec 2021 confirm that sera from both Pfizer and CoronaVac recipients, taken 56 days after the first dose (hence not yet “waned” immunity) have show very weak neutralization against omicron (in an assay with live virus)

Ep 202-2 : Encouraging data about 3rd Pfizer dose from Israel medRxiv 14 Dec:

100-fold increase in neutralization efficiency of Omicron following a third dose, with a 4-fold reduced neutralization compared to that against the Delta VOC.

But…. The durability of the effect of the third dose is yet to be determined.  

Ep 202-3: Gardner and Kilpatrick medRxiv 13 Dec estimate vaccine effectiveness (VE) against omicron, extrapolated from neutralizing antibodies.   

• For individuals with “waned immunity” after second dose VE against severe disease is significantly diminished and protection against infection, symptomatic disease and transmission is nearly eliminated.
• However, third doses significantly ameliorate these reductions but only restore protection to levels equivalent to waned protection against the Delta variant.

Ep 202-4: A nice summary in BMJ on what we know about omicron up to Dec 10.

SIDE EFFECTS OF VACCINES: focus on male and female genital and reproductive system

Ep 202-5: Nassau in BJUI Oct 2021: Relation between COVID on male genital system:

• Could androgens be involved in higher pathogenicity in men?  No clear answer:
  • Conflicting data about whether castrate, low or high testosterone levels are protective or detrimental in COVID-19.
  • This has led to investigations into potential treatment using both Androgen Depletion Therapy and Testosterone Replacement Therapy. 
  • Both are limited by adverse effects, especially in those with severe COVID-19.

• No evidence of sexual SARS-CoV-2 transmission.
• Orchitis 10-20 % of hospitalized men with severe COVID
• Erectile dysfunction: about 3 X more frequent in men after COVID
• Fertility : moderate COVID is associated with azoospermia or hypospermia in 25 % of cases, at least temporarily

Ep 202-6: Sharon Lo in Int J Impot Res 2021: Effect of COVID and mRNA on male genital system

• Similar data review on effects of COVID
• No effect of mRNA vaccine on male fertility (sperm quantity and quality) in two small studies of 40 men.
• Very rare urological side effects (0.7 %) after mRNA vaccine: lower urinary tract symptoms, hematuria, urinary infection.  
• No reported symptoms related to erectile function, ejaculatory function, or sexual function after vaccination.

Ep 207 A and B:  Reviews on the well-known adverse effects of COVID on pregnancy and newborn.    

• Much higher maternal death (2 %) than in age-matched controls (< 0.5 %)
• 5 % abortions and 25 % preterm deliveries
• Neonatal adverse outcomes included fetal distress (11%,), low birth weight (15%), APGAR <7 (19%), admission to the neonatal intensive care unit (28%) and fetal mortality (2%).
• No evidence of SARS-CoV-2 in the placenta, breast milk, umbilical cord, and amniotic fluid.  
• The risk factors associated with severe COVID-19 and the above complications are a high body-mass index (BMI), chronic hypertension, pre-eclampsia, and pre-existing diabetes, suggesting vascular changes as being the cornerstone of the severe COVID-19 course.

Ep 207-8: Review by Fei Chen in Hum Reproduct Nov 2021 shows that mRNA vaccination protects against these adverse pregnancy outcomes (Table 2).

Ep 207-9: Bowman in Reproductive Toxicology shows that Pfizer vaccine in rats had no effect on any parameter of  female fertility or prenatal and postnatal offspring development.

Ep 207-10: Udo Markett analyzes the claims that cross-reactivity with syncytin-1 could be involved in lowered female fertility by antibodies towards SARS-CoV-2, because of a small homologous (but not identical amino acid stretch).  There is no proof that SARS-CoV-2 infection or vaccination induces deleterious antibodies:

• No significantly increased risk of pregnancy loss for women with anti-SARS-CoV-2 antibodies (after infection or vaccination) has been reported.
• Pregnancy rate upon transfer of in vitro fertilized frozen embryos is not different between vaccinated or recovered anti-SARS-CoV-2 immunoreactive and non-reactive women

Ep 199-5: Alexandra Alvergne in medRxiv Dec 2021 on menstrual changes after either Pfizer or Astra-Zeneca based on survey:

• Rather common: 20 %
• Not dependent on type of vaccine
• Higher by about 40-50 % in women who were smokers or who had been COVID-infected
• Lower by 50 % in oral contraceptive users.
• Diverse experiences: from menstrual bleeding cessation to heavy menstrual bleeding. The most common words include “cramps”, “late”, “early”, “spotting”, “heavy” and “irregular”.

Ep 202-11: Victoria Male in BMJ Sept 2021 confirms that there are plenty of reports on menstrual changes during the first cycle after vaccination (both mRNA and Adeno). However:

• The pattern returns to normal in the next cycle.
• It has also been observed after other vaccinations (e.g. Papilloma virus vaccine) and it is common during SARS-CoV-2 infection (at 25 %).
• There is no evidence of effect on fertility:
  • In COVID vaccine clinical trials: the rate of (unintended) pregnancies was similar in vaccinated ad placebo group
  • In assisted reproduction clinics, fertility measures and pregnancy rates are similar in vaccinated and unvaccinated patients.   

Clearly, although it does not seem of any lasting importance, it can feed vaccine hesitancy and needs to be investigated more thoroughly.

Ep 202-12: Trogstad in Vaccine reports on slightly increased bleeding tendency after vaccination in a large Norvegian cohort (80,000)

• With mRNA vaccine 4/3416 subjects (0.2%) reported skin bleeding as a side effect, as opposed to 163 of 5132 subjects (3.2%) vaccinated with a single dose of the Astra-Zeneca OR (odds ratio) = 16.0
• Corresponding ORs for nose and gingival bleeding were 8.0 and 9.3 respectively

These data suggest that the Adenovirus vaccine, but not the mRNA may slightly elevate bleeding tendency. Hence not only in rare cases with documented thrombosis and thrombocytopenia

Some Conclusions  

1. We all need a third booster to protect us against severe outcome after omicron.  It will, however, not reduce the transmission.  Therefore, additional non-pharmacological interventions are absolutely required.
2. Severe COVID is associated with orchitis and even moderate COVID may result in lower sperm quality and erectile dysfunction.    In contrast, mRNA vaccination has no adverse effect on fertility or sexual function in men.
3. The adverse effect of COVID on pregnancy and newborns are well known. mRNA vaccines have no adverse effects on female fertility, but they may be associated with temporal menstrual disturbances, which need further investigation. 
4. Astra-Zeneca (but much less Pfizer) have been associated with mild skin, nose, periodontal bleedings.